DEPARTMENT OF HEALTH AND HUMAN SERVICES 

CENTERS FOR DISEASE CONTROL AND PREVENTION

Advisory Committee on 

Immunization Practices (ACIP)

Summary Report

June 26-27, 2019 

Atlanta, Georgia 

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Advisory Committee on Immunization Practices (ACIP) Summary Report June 26-27, 2019

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Table of Contents Page

Agenda 4-5

Acronyms 6-9

Wednesday: June 26, 2019

Welcome and Introductions 12-16

Human Papillomavirus Vaccines

 Introduction

 Background

 9vHPV Immunogenicity and Safety Trial in Mid-Adult Females

 Overview of Health Economic Models for HPV Vaccination of Mid-Adults

 Evidence to Recommendation (EtR) Framework

 Work Group Considerations and Proposed Policy Options

 Vote

16-46

Pneumococcal Vaccines

 Introduction

 Considerations for PCV13 Use Among Adults 65 Years or Older

 Summary of the Evidence to Recommendations (EtR) Framework

 Proposed Policy Options

 Vote

46-64

Combination Vaccines

 Introduction

 Summary and Relevant Evidence to Recommendation (EtR) Information

65-80

Measles Update 81-83

Zoster Vaccines

 Introduction

 Update: Safety Monitoring and Surveillance for Recombinant Zoster Vaccine (RZV)

 Herpes Zoster Work Group Summary

83-92

Pertussis Vaccines

 Introduction

 Evidence to Recommendation (EtR) Framework, Work Group Considerations, and Proposed Policy

Options

 Vote

92-98

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Thursday: June 27, 2019

Agency Updates

 Centers for Disease Control and Prevention (CDC)

 Center for Medicare and Medicaid Services (CMS)

 Department of Defense (DoD)

 Department of Veteran’s Affairs (DVA)

 Food and Drug Administration (FDA)

 Heath Resources and Services Administration (HRSA)

 Indian Health Services (I HS)

 National Institutes of Health (NIH)

 National Vaccine Advisory Committee (NVAC)

 National Vaccine Program Office (NVPO)

98-102

Influenza

 Introduction

 2018-2019 US Influenza Activity

 2018-2019 Influenza Vaccine Effectiveness

 2018-2019 Influenza Vaccine Safety

 Proposed Recommendations for 2019-2020

 Votes

102-122

Hepatitis Vaccines 

 Introduction

 Recommendations for Use of Hepatitis A Vaccine

 Votes

122-146

Meningococcal Vaccines

 Introduction

 Review of Immunogenicity of Persistence Data, GRADE, EtR, and Policy Options for MenB Booster 

Doses

 Proposed Recommendations for Use of Meningococcal Vaccines

 Votes

146-163

Dengue Virus Vaccines

 Introduction

 Dengue Epidemiology in the US

 DENGVAXIA® Phase III Clinical Trials and Long-Term Follow-Up

 Work Group Considerations and Next Steps

164-180

Certification 181

Membership Roster 182-190

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Acronyms

9vHPV 9-valent HPV 

AAFP American Academy of Family Physicians 

AAP American Academy of Pediatrics

ABCs Active Bacterial Core Surveillance 

ACA Affordable Care Act 

ACHA American College Health Association 

ACIP Advisory Committee on Immunization Practices

ACOG American College of Obstetricians and Gynecologists

ACP American College of Physicians 

ADE Antibody-Dependent Enhancement 

ADEM Acute Disseminated Encephalomyelitis 

ADVISE Agent-based Dynamic model for Vaccination and Screening Evaluation

AE Adverse Event

AFHSB Armed Forces Health Surveillance Branch 

AFIX Assessment, Feedback, Incentive and eXchange of information 

AGW Anogenital Warts 

AHIP America’s Health Insurance Plans

AI/AN American Indian/Alaskan Native 

AIM Association of Immunization Managers 

AIRA American Immunization Registry Association 

ALTS Atypical Squamous Cells of Undetermined Significance/Low-Grade 

Squamous Intraepithelial Lesions Triage Study 

Anti-HAV Serum Antibody to Hepatitis A Virus 

Anti-HBsAg Hepatitis B Surface Antigen

Anti-PA IgG Anti-Protective Antigen Immunoglobulin G 

AOA American Osteopathic Association 

APhA American Pharmacists Association 

APN Advanced Practice Nurse

APRN Advanced Practice Registered Nurse

aQIV Adjuvanted Quadrivalent Influenza vaccine 

ARFI Acute Respiratory or Febrile Illness 

ARI Acute Respiratory Illness

ASTHO Association of State and Territorial Health Officers 

ATS American Thoracic Society 

BLA Biologics License Application 

BMI Body Mass Index

CAP Community-Acquired Pneumonia 

CAPiTA Community-Acquired Pneumonia Immunization Trial in Adults 

CDC Centers for Disease Control and Prevention

CDSi Clinical Decision Support for Immunization 

CER Cost-Effectiveness Ratio

CFR Case Fatality Ratio

CIDP Chronic Inflammatory Demyelinating Polyneuropathy 

CIN Cervical Intraepithelial Neoplasia 

CISA Clinical Immunization Safety Assessment 

CISNET Cancer Intervention and Surveillance Modeling Network 

CLD Chronic Liver Disease 

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CLIA Clinical Laboratory Improvement Amendments 

CMS Center for Medicare and Medicaid Services

COI Conflict of Interest 

COID Committee on Infectious Diseases (AAP)

COPD Chronic Obstructive Pulmonary Disease

CSTE Council of State and Territorial Epidemiologists 

DC District of Columbia

DENV Dengue Virus 

DFO Designated Federal Official

DNA Deoxyribonucleic Acid 

DoD Department of Defense

DSMB Data Safety Monitoring Board 

DSTDP Division of STD Prevention 

DTaP Diphtheria and Tetanus Toxoid and Pertussis 

DVA Department of Veterans Affairs

DVD Division of Viral Diseases

EB Empirical Bayesian 

ED Emergency Department

EGL External Genital Lesions 

EHR Electronic Health Record 

EIS Epidemic Intelligence Service

ELISA Enzyme-Linked Immunosorbent Assay 

EMA European Medicines Agency 

EMR Electronic Medical Record 

EtR Evidence to Recommendation 

EU European Union 

EUA Emergency Use Authorization 

FDA Food and Drug Administration

FFS Medicare Fee-For-Service 

FHA Filamentous Hemagglutinin 

FQHC Federally Qualified Health Center 

GBS Guillain-Barré Syndrome 

GCC (Tom Harkin) Global Communications Center

GMC Geometric Mean Concentration

GMT Geometric Mean Titers 

GRADE Grading of Recommendation Assessment, Development and Evaluation 

GSK GlaxoSmithKline 

HAIVEN Hospitalized Adult Influenza Vaccine Effectiveness Network 

HAN Health Alert Network 

HAV Hepatitis A Virus

HBIG Hepatitis B Immune Globulin

HCAP Healthcare-Associated Pneumonia 

HCUP Healthcare Cost and Utilization Project 

HCP Healthcare Personnel / Providers

HCW Healthcare Workers 

HepA Hepatitis A 

HepB Hepatitis B 

HHS (Department of) Health and Human Services

HI Hemagglutinin Inhibition

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Hib Haemophilus Influenzae Type B

HIV Human Immunodeficiency Virus

HPV Human Papillomavirus

HPV-IMPACT HPV Vaccine Impact Monitoring Project 

HRSA Health Resources and Services Administration 

hSBA Human Serum Bactericidal Activity 

HZ Herpes Zoster 

ICD International Classification of Diseases 

IDCRP Infectious Disease Clinical Research Program 

ICER Incremental Cost-Effectiveness Ratio 

ICH International Conference on Harmonisation 

ICU Intensive Care Unit

IDMC Independent Data Monitoring Committee 

IDSA Infectious Disease Society of America 

Ig Immunoglobulin

IHB Immunization Healthcare Branch 

IHS Indian Health Service 

IIS Immunization Information Systems 

IIV Inactivated Influenza Vaccine 

ILI Influenza-Like Illness 

ILINet Influenza-like Illness Surveillance Network 

IM Intramuscular 

IND Investigational New Drug 

IOM Institute of Medicine 

IPD Invasive Pneumococcal Disease 

IPV Inactivated Poliovirus 

IRB Institutional Review Board

ISD Immunization Services Division 

ISO Immunization Safety Office

ITT Intention-To-Treat 

IV Intravenously 

IVE Influenza Vaccine Effectiveness 

IVIG Intravenous Immunoglobulin 

JE Japanese Encephalitis

LTFU Long-Term Follow-Up 

MAM Mid-Adult Men Study

MedDRA Medical Dictionary for Regulatory Activities 

MenB Meningococcal B

MMP Medical Monitoring Project 

MMWR Morbidity and Mortality Weekly Report

MSM Men Who Have Sex With Men 

NACCHO National Association of County and City Health Officials 

NACI National Advisory Committee on Immunization Canada

NAP National Action Plan 

NAPNAP National Association of Pediatric Nurse Practitioners 

NBPP Non-Bacteremic Pneumococcal Pneumonia 

NCEZID National Center for Emerging and Zoonotic Infectious Diseases 

NCHHSTP National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention 

NCHS National Center of Health Statistics 

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NCI National Cancer Institute 

NCIRD National Center for Immunization and Respiratory Diseases 

NDCs National Drug Codes 

NEJM New England Journal of Medicine

NFID National Foundation for Infectious Diseases 

NHANES National Health and Nutrition Examination Survey 

NHIS National Health Interview Survey 

NHRC Naval Health Research Center 

NIAID National Institute of Allergy and Infectious Diseases 

NIH National Institutes of Health

NIP National Immunization Program 

NIPP Non-Bacteremic Pneumococcal Pneumonia 

NIS-Child National Immunization Survey-Child 

NIS-Teen National Immunization Survey-Teen 

NNDSS National Notifiable Diseases Surveillance System 

NNV Number Needed to Vaccinate 

NP Nasopharyngeal 

NPCR National Program of Cancer Registries 

NVSN New Vaccine Surveillance Network 

NVAC National Vaccine Advisory Committee 

NVP National Vaccine Plan

NVPO National Vaccine Program Office 

NVSN New Vaccine Surveillance Network 

NVT Non-Vaccine Types 

NYC New York City

OASH Office of the Assistant Secretary for Health 

OB-GYN Obstetrician-Gynecologist

OHAIDP Office of HIV/AIDS and Infectious Disease Policy 

OID Office of Infectious Disease 

OIDP Office of Infectious Disease Policy and HIV/AIDS 

OP Oropharyngeal 

PA Protective Antigen 

PCP Primary Care Physician

PCR Polymerase Chain Reaction 

PCV Pneumococcal Conjugate Vaccine

PEP Post-Exposure Prophylaxis

PhRMA® Pharmaceutical Research and Manufacturers of America®

PICO Population, Intervention, Comparison, Outcomes 

PIDS Pediatric Infectious Disease Society 

PK Pharmacokinetics 

PPS Philippine Pediatric Society 

PPV Positive Predictive Value 

PrEP Pre-Exposure Prophylaxis 

PREVENT Pregnancy Influenza Vaccine Effectiveness Network 

PRNT Plaque Reduction Neutralization Test 

PRP Polyribosyl Ribitol Phosphate 

PRR Proportional Reporting Ratio 

PT Preferred Terms (MedDRA)

PRDH Puerto Rico Department of Health 

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PWHIV Persons Living With HIV 

PWID People Who Inject Drugs 

QALY Quality-Adjusted Life-Year 

QIV Quadrivalent Influenza Vaccine 

RCA Rapid Cycle Analysis

RCT Randomized Controlled Trial

RDT Rapid Diagnostic Test

RIV Recombinant Influenza Vaccine 

RNA Ribonucleic Acid 

ROA Route of Administration 

RPMS Resource and Patient Management System 

RR Relative Risk

rRT-PCR Real-Time Reverse Transcription Polymerase Chain Reaction 

RSV Respiratory Syncytial Virus 

RT-PCR Reverse Transcriptase Polymerase Chain Reaction

RZV Recombinant Zoster Vaccine 

S. pneumoniae Streptococcus pneumoniae 

SAB Spontaneous Abortion

SAE Serious Adverse Event 

SAGE Strategic Advisory Group of Experts on Immunization (WHO)

SAHM Society for Adolescent Health and Medicine 

SBA Serum Bactericidal Assay 

sBLA Supplemental Biologics License Application 

SC Subcutaneous

SCC Squamous Cell Carcinoma 

SCRI Self-Controlled Risk Interval 

SDOH Social Determinants of Health 

SES Socioeconomic Status 

SGA Small for Gestational Age 

SIDS Sudden Infant Death Syndrome 

SLIPE Sociedad Latinoamericana de Infectologia Pediatrica 

SME Subject Matter Expert

SNiPP Surveillance for Non-invasive Pneumococcal Pneumonia 

SNS Strategic National Stockpile

SSUAD Serotype-Specific Urinary Antigen Detection 

STI Sexually Transmitted Infections

Tdap Tetanus Toxoid, Reduced Diphtheria Toxoid, and Acellular Pertussis

TECs Tribal Epidemiology Centers 

TIV Trivalent Influenza Vaccine

TND Test Negative Design 

TPP Target Product Profile 

UK United Kingdom

US United States

USCS United States Cancer Statistics 

USAFSAM Air Force School of Aerospace Medicine 

US Flu VE US Influenza Vaccine Effectiveness Network

USPHS US Public Health Service 

USU Uniformed Services University 

UTD Up-To-Date 

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VA (US Department of) Veteran’s Affairs 

VAERS Vaccine Adverse Event Reporting System

VE Vaccine Efficacy

VE Vaccine Effectiveness

VFC Vaccines For Children

VICP Vaccine Injury Compensation Program 

VIS Vaccine Information Statement 

VLP Virus-Like Particles 

VRBPAC Vaccine and Related Blood Products Advisory Committee 

VRC Vaccine Research Center 

VSD Vaccine Safety Datalink

VT Vaccine Type 

VT-CAP Vaccine-Type Community-Acquired Pneumonia 

WG Work Group

WHO World Health Organization

YF Yellow Fever

ZVL Zoster Vaccine Live 

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José Romero, MD, FAAP

ACIP Chair

Amanda Cohn, MD

Executive Secretary, ACIP / CDC

Dr. Romero called to order the June 2019 Advisory Committee on Immunization Practices 

(ACIP) and welcomed those present.

Dr. Cohn welcomed everyone to the June 2019 ACIP meeting. She indicated that the 

proceedings of this meeting would be accessible to people not in attendance via the World Wide 

Web, and welcomed those who could not attend the meeting in person. She pointed out that 

multiple Centers for Disease Prevention and Control (CDC) staff were present at the entrance to

the room and at the desk outside the room to assist members of the public with questions.

She noted that handouts of the presentations were distributed to the voting ACIP members and 

were made available for others on the tables outside of the auditorium. Additionally, slides were 

made available through a ShareFile link for liaison and ex-officio members. Slides presented 

during this meeting will be posted on the ACIP website approximately three to four weeks after 

the meeting. The live webcast also will be posted in about four weeks following the meeting, and 

the meeting minutes are posted to the ACIP website generally within about 120 days following 

the meeting. Minutes from the February 2018 meeting were scheduled to be posted shortly after 

the June 2019 meeting.

To ensure the health and safety of all individuals attending this meeting, Dr. Cohn reviewed a 

few safety regulations. She explained that in the event of an emergency resulting in an 

evacuation, the procedures would be as follows: 









Those sitting in the back of the room behind the ropes were instructed to exit out the rear 

doors and across the bridge the way they came in.

Those sitting in the front of room were instructed to exit through the rear of the room, 

turn left, then proceed right down the stairs.

Everyone should locate the blue building marker sign labeled “Conference and Meeting 

Space—GCC, 2nd floor” and group together to ensure all attendees are accounted for. 

Once the premises have been secured and an “all clear” has been issued, participants 

would be permitted to re-enter the building and the meeting would resume. 

The next ACIP meeting will be convened at CDC on Wednesday and Thursday, October 23-24, 

2019. Registration for all meeting attendees is required and will open on the ACIP website when 

the Federal Register notice is posted. As a reminder, registration is now being limited so that all 

members who have registered for the meeting can participate in the meeting room. Registration 

will close when room capacity has been reached. Registration is not required for webcast 

viewing.

Call To Order, Welcome, Overview / Announcements, & Introductions 

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Dr. Cohn announced the following new and substitute Liaison Representatives:







Jeffrey Duchin, MD will be a new Infectious Disease Society of America (IDSA) 

representative along with Carol Baker, MD and the two will be alternating meetings

Clement Lewin PhD, MBA would be representing Pharmaceutical Research and 

Manufacturers of America® (PhRMA®) during this meeting

Marcus Plescia, MD, MPH would be representing the Association of State and Territorial 

Health Officers (ASTHO) during this meeting

Dr. Romero observed that this was a bittersweet meeting for those on the committee because it 

was time to say goodbye to individuals with whom they have worked for the last 4 years. He 

recognized the following retiring ACIP members:

Dr. Echezona Ezeanolue

Dr. Ezeanolue, from the University of Nevada, has been with ACIP since 2015. He has served 

on the General Best Practices Work Group (WG) and Hepatitis WG. He was Dr. Romero’s 

mentee during his first year. Dr. Ezeanolue said that it had been an honor for him as someone 

who did not grow up in this environment to see how policies are made in a way that allows 

science to trump politics. For him, serving on ACIP for the past 4 years has been a great 

learning experience.

Dr. Kelly Moore

Dr. Moore, from Vanderbilt University, is a rival for Art Reingold for the award for most 

Chairmanships on ACIP having served as chair on the Combination Vaccines, Hepatitis, 

Mumps, and Zoster WGs and as a member of the General Best Practices and Meningococcal 

WGs. Dr. Moore has tremendous experience in public health and has brought that perspective 

to ACIP. Dr. Moore said that she attended her first ACIP meeting in 2005 as a member of the 

audience and has not missed a meeting since. Serving as a liaison representing Association of 

Immunization Manager (AIM) for 5 years and the last 4 years as a voting member has been the 

best privilege of her professional life. She said that it has been a delight to get to know each of 

them, and emphasized that she always will be proud of the quality of the work they have done.

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Dr. David Stephens

Dr. Stephens, from Emory University School of Medicine, has served as Chair of the Anthrax 

and Meningococcal WGs. While Dr. Stephens has a very quiet demeanor, he has had a very 

strong influence on the group bringing his thoughtful and measured perspective to topics ACIP 

has addressed. Dr. Stephens thanked ACIP and the members for the last 4 years, which he 

said was wonderful to be a part of. ACIP is comprised of a fine set of individuals and he 

appreciated the opportunity to have been a part of the group. He also thanked CDC and the 

ACIP leadership and said he looked forward to continuing to promote vaccines and vaccine 

policy.

Dr. Chip Walter

 

Dr. Walter, from Duke University School of Medicine, has served as Chair of the Influenza and 

Flavivirus WGs and as a member of the Dengue WG. The Influenza WG is one of the most 

complicated, has had to analyze a lot of data, and has had to make decisions based on very 

little data sometimes. Dr. Walter said that it has been a honor and a highlight of his professional 

career to have served as a member of ACIP for the past 4 years. He believes that ACIP does 

fantastic work evaluating all of the available information and trying to make the best 

recommendations for the use of vaccines for controlling vaccine-preventable diseases. He 

recognized that throughout the past 4 years, he has had the opportunity to work with incredible 

people from CDC who have provided information and resources to assist ACIP with its 

deliverables. Furthermore, he recognized the fantastic opportunity to have worked alongside of 

a number of talented and diverse ACIP members. He expressed his gratitude for having had 

this once in a lifetime experience.

Dr. Cohn noted that these 4 members began their ACIP experience at the same time that she 

started her experience in the role of Executive Secretary, so she felt like she “grew up” with 

them and appreciated their leadership and mentorship of her over the last 4 years. She 

presented each with a framed Dr. Seuss vaccine poster.

As stated in the ACIP charter, Dr. Cohn reminded everyone that the purpose of the ACIP 

committee is as follows: 

 “Committee deliberations on the use of vaccines to control disease in the U.S. shall 

include consideration of disease epidemiology and burden of disease, vaccine efficacy 

and effectiveness, vaccine safety, the quality of evidence reviewed, economic analyses, 

and implementation issues.”

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



“The committee may revise or withdraw their recommendations regarding a particular 

vaccine as new information on disease epidemiology, vaccine effectiveness or safety, 

economic consideration or other data become available.”

“Under provisions of the Affordable Care Act (ACA) . . . immunization recommendations 

of the committee that have been adopted by the Director of the CDC must be covered by 

applicable health plans”

Dr. Cohn indicated that to improve the clarity of ACIP’s recommendations, recommendations 

based on clinical decision-making between the patient and provider will be referred to beginning 

with this meeting as “shared clinical decision-making” recommendations. This differs slightly 

from the previous phrasing of “individual clinical decision-making,” but the intent is the same. 

“Shared clinical decision-making” is a better understood concept among clinicians and better 

describes that this is not a decision made by an individual, but instead is a decision made 

between two people for an individual.

ACIP is, at its heart, a public body. Engagement with the public and transparency in ACIP’s 

processes is vital to the Committee’s work. As part of ACIP’s commitment to continuous 

improvement, ACIP recently strengthened its oral and written public comment process to 

accommodate increased public interest in ACIP’s work, maximize opportunities for comment, 

and make public comment more transparent and efficient. Dr. Cohn indicated that for this 

meeting, there would be oral public comment periods prior to the votes for each day. The oral 

public comment were scheduled to occur at 1:30 PM each day of the meeting.

To create a fairer and more efficient process for requesting to make an oral comment, people 

interested in making an oral comment were asked to submit a request online in advance of the 

meeting. Priority is given to these advance requests, and if more people request to speak than 

can be accommodated, a blind lottery is conducted to determine who will be the speakers.

Speakers selected in the lottery for this meeting were notified in advance of the meeting. Dr. 

Cohn requested that the public comment speakers identified for this meeting sign in at the 

information table outside the main auditorium to confirm their presence.

For written public comments, ACIP is using a docket on regulations.gov where any member of 

the public can submit a written comment. This process allows for the ability to submit longer 

comments and the ability to include attachments, comments to be visible to the public, and a 

longer window for comment submission. Comments may now be submitted up to 48 hours 

following the end of the meeting, and all comments submitted by 72 hours of the meeting will be 

made available to the ACIP members prior to the meeting. At the time of this meeting, the 

written comment docket was still open. Using docket ID CDC-2019-0028, those interested were 

invited to submit a comment at regulations.gov. Dr. Cohn indicated that the docket would remain 

open for 48 hours following the end of the meeting. This information also can be found in the 

Federal Register notice announcing ACIP meetings and on the ACIP meeting website. She 

encouraged everyone to access and read the public comments posted.

As noted in the ACIP Policies and Procedures manual, members of the ACIP agree to forgo 

participation in certain activities related to vaccines during their tenure on the committee. For 

certain other interests that potentially enhance a member’s expertise while serving on the 

committee, CDC has issued limited conflict of interest (COI) waivers. Members who conduct 

vaccine clinical trials or serve on data safety monitoring boards (DSMBs) may present to the 

committee on matters related to these vaccines, but are prohibited from participating in 

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committee votes on issues related to those vaccines. Regarding other vaccines of the 

concerned company, a member may participate in discussions with the provision that he/she 

abstains on all votes related to the vaccines of that company. At the beginning of each meeting

and prior to each session, ACIP members will state any COIs. 

Detailed instructions for submission of names of potential candidates to serve as ACIP 

members is available on the ACIP website. Applications for ACIP membership originally were 

due no later than July 1, 2019 for the 4-year term beginning July 2020. However, that has been 

extended to August 1, 2019.

Dr. Cohn announced that Dr. Narayan Nair would be retiring as a CAPT in the United States 

Public Health Service (USPHS) as well as his position as Division Director/Chief Medical Officer

in the Division of Injury Compensation Programs in the Healthcare Systems Bureau of the

Health Resources and Services Administration (HRSA). Therefore, this would be his last ACIP 

meeting. He has served in the role as the HRSA liaison for the last 5 years. CDC and ACIP 

have appreciated his participation.

Dr. Romero conducted a roll call to determine whether any ACIP members had COIs. No 

member had any COI to declare. He then requested that the Liaison and Ex Officio members 

introduce themselves. A list of Members, Ex Officio Members, and Liaison Representatives is 

included in the appendixes at the end of the full minutes from the June 2019 ACIP meeting.

Introduction

Peter Szilagyi, MD, MPH

Chair, ACIP HPV Vaccines WG

Dr. Szilagyi reminded everyone that these are the current recommendations for HPV 

vaccination in the US: 



•

•



•

•

•



Routine vaccination

Age 11 or 12 years 

Vaccination can be started at age 9 years 

Catch-up vaccination 

Females through age 26 years

Males through age 21 years 

Certain populations through age 26 years*

Males aged 22 through 26 years may be vaccinated

[*Men who have sex with men (MSM), transgender persons, and persons with certain immunocompromising conditions; 

MMWR 2014;63 (RR05); MMWR 2015;64:300-4; MMWR 2016; 65:2105-8] 

Human Papillomavirus (HPV) Vaccines

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He indicated that the following policy questions for HPV vaccination would be presented to ACIP 

for a vote during this session: 





Should catch-up HPV vaccination be recommended for primary prevention of HPV 

infection and HPV-related disease for all persons through age 26 years?

Should catch-up HPV vaccination be recommended for primary prevention of HPV 

infection and HPV-related disease for all persons aged 27 through 45 years?

The reason the WG is considering these two issues is that with regard to harmonization, the 

WG had discussions in 2017 and 2018 related to simplification of the vaccination schedule. 

Related to vaccination of adults older than 26 years of age, the manufacturer filed an application 

in April 2018 to expand the age indication for 9-valent HPV vaccine (9vHPV) from age 9-26 

years to age 9-45 years. This was approved by the Food and Drug Administration (FDA) in 

October 2018. 

HPV vaccine sessions at 3 ACIP meetings have focused on the expanded age indication. In 

June 2018, there was an overview and presentation on the history of application for the 

expanded age licensure, a review of HPV epidemiology, and the natural history and burden of 

disease. The manufacturer presented clinical trial data submitted in the Supplemental Biologics 

License Application (sBLA) for 9vHPV in adults aged 27-45 years.

In October 2018, presentations included a review of the regulatory basis for licensure for the 

expanded age range, several aspects of the US HPV vaccination program, including vaccination 

coverage and current evidence of impact on infection and disease. There was a review of HPV 

epidemiology, sexual behavior, and post-licensure effectiveness. In addition, there was a brief 

update on global HPV vaccination and vaccine supply, highlighting the current demand/supply 

imbalance. Grading of Recommendation Assessment, Development and Evaluation (GRADE) 

was presented for efficacy, immunogenicity, and safety of HPV vaccine for adults older than 26 

years of age. There also was a summary of the health economic analyses, and initial policy 

considerations discussed by the HPV Vaccines WG were presented. At that time, the WG 

introduced the option of a recommendation for individual clinical decision-making.

In February 2019, the WG presented an overview of natural history, the impact and costeffectiveness of mid-adult HPV vaccination using the HPV Agent-based Dynamic model for 

Vaccination and Screening Evaluation (ADVISE) model, and health economic results from 5 

models being considered for this policy question. In addition, the WG presented information on 

patient values and acceptability and findings from program and vaccine provider surveys about 

the expanded age indication for HPV vaccination. Updated considerations and policy options, 

based on continued WG discussions and deliberations, were presented as well. 

Since the February 2019 ACIP meeting, the WG has continued to review updated results from 

models of HPV vaccine impact and health economics. They heard an industry presentation on 

the global HPV vaccine supply and the current shortage. They had a preliminary review of data 

on HPV vaccination in HIV-infected adults, as well as data on HPV vaccination post-treatment 

for anogenital disease. Both topics require additional review of data and discussion, which the 

WG will consider in the future. Data from the recently completed 9vHPV vaccine 

immunogenicity and safety trial in adults were presented to the WG in May 2019, which the 

ACIP will hear during this session. The WG also reviewed the Evidence to Recommendations

(EtR) documents and continued to discuss recommendation options. 

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Regarding recommendations for vaccination of adults older than age 26 year, during the 

February 2019 meeting, the options presented by the WG for consideration included Clinical 

Decision-Making or Not Making a Recommendation. Importantly, no members of the WG were 

in favor of a Routine Universal Recommendation. Therefore, this was not discussed as an 

option. After the February 2019 ACIP meeting, there were discussions with the ACIP 

Secretariat, EtR consultants, and the WG. Options being proposed during this session included

Shared Clinical Decision-Making or Do Not Recommend the Intervention. 

The WG reached consensus on the first question, “Should catch-up HPV vaccination be 

recommended for primary prevention of HPV infection and HPV-related disease for all persons 

through age 26 years?” For vaccination of adults older than 26 years of age, two options would 

be proposed: a majority and a minority opinion from the WG.

This session included the following presentations: Background, 9vHPV Immunogenicity and 

Safety Trial in Women Age 27-45 Years, Overview of Health Economic Models for HPV 

Vaccination of Mid-Adults, Evidence to Recommendations, and WG Considerations. 

Background: HPV Vaccines Session

Lauri Markowitz, MD

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

In this presentation, Dr. Markowitz provided some additional background for this session. 

Specifically, she provided background for the two policy issues being considered: harmonization 

of catch-up vaccination through age 26 years and vaccination of adults older than age 26 years.

She also included an update on the global HPV vaccine landscape. 

This table shows vaccines licensed in the US, the manufacturer, and licensure ages before 

October 2018: 

Vaccine HPV Types Manufacturer Licensure Ages

Bivalent (2vHPV) 16,18 GlaxoSmithKline Females 9-25 

years

Quadrivalent 

(4vHPV)

6,11,16,18 Merck & Co. Females and 

males 9-26 years

9-valent (9vHPV) 6,11,16,18, 

31,33,45,52,58

Merck & Co. Females and 

males 9-26 years

Although three vaccines are licensed, since the end of 2016, only 9vHPV vaccine has been 

distributed in US. However, 2vHPV and 4vHPV vaccines continue to be available in other 

countries. In October 2018, 9vHPV vaccine was licensed through age 45 years. Dr. Markowitz 

emphasized that although 9vHPV vaccine was recently licensed through this age in the US, all 

three HPV vaccines have been licensed through age 45 or older in other countries. However, no 

country has a public health HPV vaccination program targeting adults older than age 26 years.

She again reviewed the current recommendations.

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Vaccination for females was recommended in 2006. At that time, HPV vaccine was licensed

only in females. Routine vaccination of males was recommended in 2011. Vaccination was first 

recommended as a 3-dose schedule. A 2-dose schedule was recommended in 2016 for those 

starting the vaccination series before age 15 years. 4vHPV was the first vaccine licensed and 

recommended in 2006, bivalent in 2009, and 9-HPV in 2015. Almost all vaccine used in the US 

was 4vHPV vaccine through 2015. After 2016, as mentioned earlier, only 9vHPV vaccine has 

been distributed in the US. 

Data from the National Immunization Survey (NIS)-teen among adolescents aged 13-17 years

showed coverage increasing gradually in females from 2006-2017. Up-to-date (UTD) is the 

measure that has been used since the 2-dose recommendation for persons starting vaccination 

before age 15. In 2017, at least 1-dose coverage for females was 69% and UTD was 53%. 

Coverage for males has increased more rapidly than for females since the 2011 

recommendation. At least 1-dose coverage was 63% in 2017, almost similar to females, and 

UTD coverage was 44%. [Adapted from Walker et al. MMWR 2018; NIS-Teen; Revised 

definition of adequate provider data in 2013].Understanding coverage is important, as this 

impacts some inputs to the models. In spite of coverage being lower than target goals, dramatic 

decreases in vaccine type HPV prevalence and other endpoints have been observed in the US. 

These were detected within 4 years of the program introduction and further reductions have 

been observed in subsequent years 

In terms of why there are different catch-up ages in the current recommendations for males and 

females, routine vaccination for males was considered after 4vHPV vaccine was licensed for 

use in males and data were available on efficacy for prevention of anal precancers in males.

ACIP considered policy for males using GRADE, including health economic analyses. These

health economic models showed that inclusion of males in the vaccination program was less 

cost-effective than female vaccination and that vaccination becomes less cost-effective with 

increasing age at vaccination. Vaccination of males was recommended at age 11 or 12 years, 

as for females, but catch-up was recommended through age 21. ACIP considered health 

economic modeling data when recommending the age for catch-up vaccination. 

There has been increasing interest from partners and stakeholders in harmonizing the upper 

age for catch-up recommendations across genders for simplification of the vaccination 

schedule. In 2017-2018 before CDC awareness of the manufacturer application to FDA for the 

9vHPV vaccine expanded age range, the ACIP HPV Vaccines WG was considering 

harmonization of catch-up recommendations across genders through age 26 years. The WG 

delayed consideration of harmonization after the FDA agreed to an expedited review for the 

expanded age application in April 2018. At that time, it was unclear what health economic 

analyses would show for adult vaccination, and they wanted to avoid multiple recommendation 

changes in one year. The health economic analyses have been much more challenging than 

anticipated; however, the WG now is ready to move forward on both harmonization and adult 

vaccination decisions.

Regarding the WG’s deliberations on the second policy question being considered during this 

session pertaining to vaccination of adults older than age 26 years, the WG also considered this

policy decision harmonized across genders. Over the past year, the WG reviewed a wide range 

of data. Dr. Markowitz highlighted that, as presented during past ACIP meetings, there is 

uncertainty about some aspects of HPV natural history. The WG considered the results from 5 

health economic models. Three models were used initially and 2 additional models were 

included to inform policy after October 2018. CDC’s desire to include additional models was due 

to the disparate results obtained across the models initially considered. Modelers and the

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ACIP/CDC economic team have been working hard over the past year to understand the 

modeling results. Of the 5 models, 4 predict high cost per quality-adjusted life-year (QALY) for 

expanding the catch-up age. The presentations for this session were intended to summarize 

data presented to ACIP over the last year, much of which is summarized in the following EtR 

presentation. The only new data were in the health economic presentation, which includes some 

new modeling data and new data from a 9vHPV vaccine immunogenicity and safety trial. 

As a reminder, licensure of 9vHPV vaccine for use through age 45 years was based on results 

of a randomized controlled trial (RCT) of 4vHPV vaccine that included women aged 27-45 

years; observational follow-up through 10 years in a subset of women in the base study; a 

cross-study immunogenicity analysis showing statistical non-inferiority of immune responses to 

4vHPV vaccine in males aged 27-45 years compared with males aged 16-26 years, the age in 

which efficacy was demonstrated; and extrapolation of these data to 9vHPV vaccine in 

individuals aged 27-45 years [Munoz et al. Lancet 2009; Castellsague et al. Br J Cancer 2011 

(end of study results); Luna et al. PLoS One 2013 (6 year follow-up); Luxembourg (10 year 

follow-up presented at ACIP June 2018); Giuliano et al. Vaccine 2015; Giuliano et al. N Engl J 

Med 2011; Palefsky et al. N Engl J Med 2011; https://www.fda.gov/downloads/BiologicsBlood 

Vaccines/Vaccines/ApprovedProducts/UCM622941.pdf].

GRADE for adult vaccination was presented to ACIP in October 2018. The GRADE evidence 

tables included data for 2vHPV and 4vHPV immunogenicity, efficacy, and safety in adults aged 

27-45 years*. The WG updated the GRADE tables in June 2019 to include data from the 9vHPV 

immunogenicity and safety trial in women age 27-45 years described in the next presentation 

[GRADE: Grading of Recommendations, Assessment, Development and Evaluation 

https://www.cdc.gov/vaccines/acip/recs/grade/about-grade.html; *Meites, presentation at 

October 2018 ACIP meeting; +Luxembourg, presentation at June 2019 ACIP meeting].

To end, Dr. Markowitz mentioned some aspects of the global landscape for HPV vaccines. This 

also was discussed briefly during the October 2018 ACIP meeting. There were just 96 (50%) of 

countries with HPV vaccine in the National Immunization Program (NIP) as of early 2019. Most 

of the countries with the highest burden of cervical cancer have not yet introduced vaccine.

There is a global HPV vaccine demand/supply imbalance, which is outlined in a World Health 

Organization (WHO) publication. As background, the WHO issued HPV vaccination 

recommendations for the first time in 2009 for a single age cohort of girls. In 2016, this 

recommendation was modified to include multi-age cohort vaccination for girls aged 9-14 years 

in the first year of vaccine introduction for greater and faster impact of the vaccination program. 

This recommendation, along with more country interest in introduction of HPV vaccine, has 

increased demand. Gavi funding for HPV vaccination for eligible countries started in 2012. Gavi 

procures bivalent and quadrivalent HPV vaccines. The current HPV vaccine demand/supply 

imbalance is projected to last for 3-5 years until there is more manufacturing capacity by the two

current manufactures and until other manufactures in late stages of vaccine development can 

bring their products to market. This will delay introduction in some low, middle, and high income 

countries and will prevent multiage cohort vaccination. No vaccine shortage is anticipated in the

US. 

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The global HPV vaccine supply was discussed during the WHO Strategic Advisory Group of 

Experts on Immunization (SAGE) meeting in October 2018. The following statement was 

included in the published SAGE report: 

“Concerned about the impact of a constrained HPV vaccine supply forecast until at least 

2024, SAGE urged that a globally more equitable distribution of the available doses be 

encouraged to ensure optimal global public health access to the vaccine.” 

There are ongoing discussions at WHO and Gavi about vaccination strategies and allocation of 

vaccine during the supply shortage [Weekly Epidemiological Record 2018;93:661-80]. 

Dr. Markowitz indicated that this short update on the global demand/supply imbalance was 

presented to ACIP during this session for general awareness, and because some WG members 

considered this in discussions of policy options for vaccination of adults older than 26 years. 

In closing, she reminded everyone that the two policy issues to be considered during this 

session included harmonization of catch-up vaccination through age 26 years, and vaccination 

of adults older than age 26 years. 

9vHPV Immunogenicity and Safety Trial in Mid-Adult Females

Alain Luxembourg, MD, PhD 

Director, Clinical Research

Merck Research Laboratories

Dr. Luxembourg briefly recapped what was presented to ACIP a year ago as well as Merck’s 

new clinical trial, Protocol 004, which is a trial of the 9vHPV vaccine among women 16-45 years 

of age.

In terms of clinical trial information, the 4vHPV vaccine is highly efficacious to prevent 

HPV6/11/16/18-related persistent infection and disease regardless of age. The women tested 

were 16-45 years of age. There was high efficacy across the entire age range, which is a very 

consistent feature of the clinical trials. Also shown was that protection is durable. In women 27-

45 years of age, protection lasts at least 10 years based on clinical trials. Regulatory agencies

have concluded that data from the 4vHPV vaccine efficacy and immunogenicity results can be 

extrapolated to the 9vHPV vaccine. This is based on the fact that both vaccines are 

manufactured using the same process, share the same virus-like particles (VLPs) for 

HPV6/11/16/18 and are manufactured using similar processes and show consistent success in 

efficacy and immunogenicity bridging studies of 4vHPV and 9vHPV vaccines across age and 

gender.

Based on clinical trial results, the FDA and other regulatory agencies have granted an indication 

for the 9vHPV vaccine in adults over 26 years of age. In the US, the 9vHPV vaccine age 

indication was expanded from 9-26 years to 9-45 years in October 2018 following priority review 

by the FDA based on 4vHPV vaccine efficacy data.

9vHPV vaccine is indicated in girls/women 9-45 years of age in Canada and Australia and 

individuals from the age of 9 years in the European Union (EU). The European Medicines 

Agency (EMA) requested a clinical study to compare 9vHPV vaccine safety and immunogenicity 

in women 27-45 years of age compared to women 16-26 years of age as a post-licensure 

commitment, which Dr. Luxembourg presented during this meeting.

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High efficacy of 4vHPV vaccine was shown across the entire 24-45 year age range in the

FUTURE III Study for the endpoints of HPV6/11/16/18-related 6-month persistent infection, 

cervical intraepithelial neoplasia (CIN), and condyloma and HPV6/11/16/18-related Pap test 

abnormalities. Similar efficacy was shown in both the 24- to 34-year and the 35- to 45-year age 

strata. There was no statistical difference between the efficacy in these two ages for two 

different endpoints. There are a substantial number of endpoints in the placebo groups showing 

a high number of cases of infections [Castellsague et al. Br J Cancer 2011; 105:28-37].

Protocol 004 was a 9vHPV vaccine immunogenicity and safety study in women 16-45 years of 

age split into 2 cohorts: 1) 642 women 27 to 45 years of age; and 2) 570 women 16 to 26 years 

of age (control group). This was an open-label, 7-month study in which all participants received 

9vHPV vaccine at Day 1 and Months 2 and 6. The goal was to examine the immunogenicity of 

the 3-dose regimen at Day 1 and Month 7. Safety was assessed in the same way it has been in 

other studies of the 9vHPV vaccine. The primary objective was to demonstrate non-inferiority of 

geometric mean titers GMTs at Month 7 (one month after the last dose) for the 7 high-risk types 

in the vaccine. The non-inferiority criterion required a less than a 2-fold decrease in women 27-

45 years of age compared to women 16-26 years of age. This study design was agreed to with 

the regulators.

Regarding the analysis of the primary objective, the non-inferiority criterion was met for all 7 

high-risk HPV types with GMT ratios (women 27-45 yrs / women 16-26 yrs) at approximately 0.7 

for each HPV type, similar to what has been observed for 4vHPV vaccine. The lower bound of 

the 95% confidence interval of the GMT ratio was approximately 0.6 for each HPV type. The 

non-inferiority criterion required that the lower bound be greater than 0.5, so this criterion was 

met and the primary objective was met. Seropositivity rates at Month 7 were greater than 99% 

for the 9 HPV types in the vaccine. Analyses by age strata showed that immunogenicity was 

very robust regardless of age. There was a trend for GMTs to decrease with age at vaccination, 

which is common with many vaccines and also has been seen with the 4vHPV vaccine 

previously. As mentioned earlier, efficacy of 4vHPV vaccine in clinical studies was always high 

across the 16-45-year age range.

In terms of safety, there was no substantial difference between the two age groups. Most 

adverse events (AEs) were injection-site AEs. There were no vaccine-related serious adverse 

events (SAEs) or deaths. The most common injection-site events were pain, swelling, and 

erythema. The frequencies of AEs at the injection site were similar between the two age groups 

and there was no statistical difference between the two groups.

In conclusion, most women 27-45 years of age are susceptible to infection by HPV types 

covered by the 9vHPV vaccine. The 4vHPV vaccine is highly efficacious in women 16-45 years 

of age, regardless of age and provides durable protection up to at least 10 years. The 9vHPV 

vaccine is highly immunogenic in women 27-45 years of age. Seroconversion rates were 

greater than 99% for the 9 HPV types. The 9vHPV vaccine induces HPV antibody responses in 

women 27-45 years of age that are non-inferior to responses in women 16-26 years of age. 

Efficacy in women 27-45 years of age was previously inferred based on the overall 4vHPV and 

9vHPV vaccine clinical data. This result further supports the efficacy of the 9vHPV vaccine in 

women 27-45 years of age. The 9vHPV vaccine is generally well-tolerated in women 27-45 

years of age. The overall conclusion is that collectively, all of these data support the clinical 

benefit of the 9vHPV vaccine in individuals 27 to 45 years of age.

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Overview of Health Economic Models for HPV Vaccination of Mid-Adults

Harrell Chesson, PhD

Division of STD Prevention

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

Dr. Chesson reminded everyone of the history of the health economic analyses of mid-adult 

HPV vaccination for ACIP. In October 2018, there was a summary presentation of the results 

from 3 models (HPV-ADVISE, Simplified, Merck) that illustrated great differences in the model 

results. Subsequently, there was a post-meeting request to the Cancer Intervention and 

Surveillance Modeling Network (CISNET) modeling group to help try to understand the 

differences. In February 2019, there were two health economics presentations. Dr. Brisson 

presented the HPV-ADVISE model and there was a summary presentation of the results from 5 

models, 3 from October plus 2 from the CISNET group. Since February 2019, all of the models 

have completed the CDC economic review process in accordance with the ACIP Guidance for 

Health Economic Studies and there is now a better understanding of the differences in the 

model results.

During this session, Dr. Chesson presented an overview of the 5 available models; showed 

results from these models that could inform both policy considerations (harmonization of catchup vaccination through age 26 years; vaccination of adults older than age 26 years); and 

discussed the reasons for the differences in the model results. The models available to inform 

mid-adult HPV vaccination policy decisions in the US include the following:











HPV-ADVISE model (Laval University / CDC)

Simplified model (CDC)

Merck model

CISNET Harvard model

CISNET Policy1-Cervix (Cancer Council New South Wales)

All 5 models include a wide range of health outcomes that can be prevented by HPV 

vaccination, including cervical precancers and cancer, other HPV-associated cancers (anal, 

vaginal, vulvar, penile, oropharyngeal), and anogenital warts. All incorporate current medical 

cost estimates for HPV-associated cancers, account for “herd effects” on mid-adults from the 

existing vaccination program, examine a long time horizon (~100 years or more), and exclude 

productivity costs. The 5 models differ in terms of structure, calibration to fit available data, 

cervical cancer screening assumptions, vaccine uptake assumptions for mid-adults, natural 

history of HPV parameters (e.g., natural immunity after HPV acquisition and clearance), and in 

how HPV transmission dynamics are characterized (e.g., rate of acquisition of new sex partners 

by age).

Regarding calibration, one important point is that the HPV-ADVISE model uses the 50 bestfitting parameter sets used for analysis and the other models use a single best-fitting parameter 

set used for analysis. Regarding natural immunity assumptions, the models differ in the percent 

of people who have natural immunity after infection and clearance and in the degree and 

duration of protection of natural immunity.

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In terms of the current program, all 5 models give a relatively favorable cost-effectiveness 

estimate. The cost per QALY gained by vaccination ranges from less than zero in the HPVADVISE model, indicating that the program is cost-saving, to just under $35,000 in the CISNET 

Harvard model.

With respect to the comparisons that were made to inform the policy considerations for this 

session, for harmonization of catch-up vaccination through age 26 years the models assessed 

vaccination through age 26 years for all persons versus the current program. For vaccination of 

adults older than age 26 years, two key comparisons were made. First, the model looked at 

expanding vaccination to age 30 years versus maintaining the current program. Second, the 

model considered vaccination through age 45 years versus the current program. The modelers 

examined a wide range of other scenarios, such as incremental analyses and increasing the 

cutoff age from 30 to 35 and 40. However, Dr. Chesson did not show those results during this 

session.

In terms of harmonization of catch-up vaccination through age 26 years focusing primarily on 

results from the HPV-ADVISE model, the estimated number needed to vaccinate (NNV) in the 

current program versus no vaccination is 9 for anogenital warts, 22 for CIN, and 202 for HPVassociated cancers. For harmonization of catch-up vaccination through age 26, when all 50 

parameter sets are applied, the NNV is 140 for anogenital warts, 430 for CIN, and 7590 for 

HPV-associated cancers. Using the 22 sets with faster progression and lower natural immunity 

the NNV is 40 for anogenital warts, 450 for CIN, and 3260 for HPV-associated cancers. Using 

the 28 sets with slower progression and higher natural immunity, the NNV is 840 for anogenital 

warts, 340 for CIN, and 8200 for HPV-associated cancers. The results are more favorable for 

harmonization at age 26 when using the parameter sets with faster progression and lower 

natural immunity.

Regarding the cost-effectiveness of harmonization of HPV vaccination, the HPV-ADVISE model 

predicts that the current program is cost-saving. When the analysis is limited to the parameter 

sets with fast progression and lower natural immunity, the cost per QALY gained is roughly 

$178,000 for harmonization at age 26 and over $400,000 at age 30 years. When the analysis is 

limited to the slower progression and higher natural immunity scenarios, no cost per QALY 

could be estimated for harmonization at age 26 because the model could not consistently find 

significant health benefits at the population level with this strategy. In this scenario, the cost per 

QALY gained by harmonization at age 30 was about $2.3 million. In terms of the estimated 

impact on the cost of the HPV vaccination program, the long-term costs are expected to 

increase by only 5% or less based on estimates from the Simplified Transmission Model under 

the uptake assumptions used in that model.

In terms of vaccination of adults older than 26 years of age, the NNV to prevent one case of 

disease from the HPV-ADVISE model in the current program versus no vaccination is again 9 

for anogenital warts, 22 for CIN, and 202 for HPV-associated cancers. For harmonization of 

catch-up vaccination through age 45, when all 50 parameter sets are applied, the NNV is 390 

for anogenital warts, 860 for CIN, and 7690 for HPV-associated cancers. Using the 22 sets with 

faster progression and lower natural immunity the NNV is 120 for anogenital warts, 800 for CIN, 

and 6500 for HPV-associated cancers. Using the 28 sets with slower progression and higher 

natural immunity, the NNV is 870 for anogenital warts, 880 for CIN, and 8580 for HPVassociated cancers. The results are much higher than for the current program.

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Regarding the estimated impact of HPV vaccination in terms of the percentage in disease 

incidence, presented by Dr. Brisson in February 2019, there is very little incremental benefit at 

the population level in terms of the impact of the current program and the impact when 

extending the current program to include mid-adults through age 45 years. For example, for 

cervical cancer the model estimates that current program over 100 years will avert about 

650,000 cases and that adding the mid-adult strategy through age 45 would avert an additional 

3000 cases.

This table shows the cost-effectiveness of vaccination of adults through 30 years of age versus 

the current program and through 45 years of age versus the current program for all 5 models:

Adult Vaccination 

Strategy

Model

HPVADVISESimplified Merck CISNET 

(Harvard) 

CISNET

(Policy1-

Cervix)

Through age 30 years 

(vs. current program)

$830,000 $587,600 $81,200 $627,700 $341,100

Through age 45 years

(vs. current program)

$1,471,000 $653,300 $117,500 $440,600 $315,700

As a reminder, the HPV-ADVISE model uses results from the 50 parameter sets. However, if it 

is limited to the parameter sets that have the faster progression and lower natural immunity, the 

cost per QALY gained is lower. Conversely, when limited to the parameters that have slower 

progression and higher natural immunity, the costs per QALY estimates are higher. As noted in 

February 2019, a distinguishing feature of the CISNET model results is that the cost per QALY 

gained from vaccination through age 45 years is lower than through age 30 years. This arises 

likely because of herd effects of the existing program on mid-adults.

The estimate in the Simplified model has changed since the February 2019 presentation. The 

Simplified model now takes into account the ongoing HPV vaccination program. The cost per 

QALY gained through age 30 was $265,200 and now is $587,600 and through age 45 was 

$417,200 and now is $653,300. The magnitude of this increase is consistent with what would be 

expected based on the other models, showing the importance of accounting for historic 

vaccination coverage. The Merck model results are now somewhat lower than presented in 

February 2019, owing to a series of minor changes. The cost per QALY gained through age 30 

was $105,100 and now is $81,200 and through age 45 years was $149,100 and now is 

$117,500.

Identified factors that may account for differences in model results include uncertainties about 

HPV natural history, including natural immunity following clearance of infections and burden of 

disease caused by new HPV infections after age 26 years; degree of herd protection from the 

existing HPV vaccination program; cervical cancer screening assumptions; health economic 

assumptions; and deaths from undiagnosed cancer. The first three factors were discussed 

during the February 2019 meeting. In the interest of time, Dr. Chesson did not revisit them and 

referred everyone to the supplemental slides for additional information. However, he did further 

discuss health economic assumptions and deaths from undiagnosed cancer.

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ACIP/CDC economic reviewers asked the modelers to examine a set of results when using a 

standardized list of health economic parameters regarding medical treatment costs of the HPVassociated outcomes and QALY assumptions. In terms of the cost-effectiveness of vaccination 

of adults through age 45 years versus the current program, there was a somewhat large relative 

increase in the Merck estimate (base case of $117,500 versus $172,000 using standard health 

economic parameters). However, in terms of the absolute differences across the models, these 

parameters did not make that much of a difference.

Deaths from undiagnosed cancer was recently identified as a factor that may be accounting for 

some of the differences across the models. In the Merck model, each year in the absence of 

vaccination, there would be almost 10,000 deaths due to diagnosed HPV cancers. These 

results are fairly consistent with the other models. The Merck model also estimates that about 

24,000 deaths would be attributable to undiagnosed HPV cancer each year. That works out to 

about 71% of the HPV cancer deaths being attributable to undiagnosed cases. With the 

exception of the CISNET Harvard cervical cancer model in which 16% of the cervical cancer 

deaths were attributable to undiagnosed cancers, none of the other models had undiagnosed 

cancer deaths in the analysis. It is important to note that the 71% Merck value and the 16% 

CISNET Harvard value are outputs of these models; whereas, the 0% values arise from 

assumptions of the modelers in the HPV-ADVISE, Simplified, and CISNET Policy1-Cervix 

models that there are no deaths due to undiagnosed cancers.

A lot of the data about cancer incidence in the models come from cancer registries. If the 

registries have good completeness, a large number of deaths due to undiagnosed cancers 

would not be expected. CDC’s US Cancer Statistics (USCS) website has a quote stating that, 

“After years of analyzing completeness of case ascertainment, CDC has determined that NPCR 

registries consistently deliver high-quality, complete data.”

In terms of the results from the Merck model regarding the cost-effectiveness of vaccination 

through age 45 years versus the current program, the base case result is $117,500 per QALY 

gained. The cost per QALY is $202,200 when deaths due to undiagnosed cancer are excluded 

and $428,900 when deaths due to undiagnosed caner are excluded and the standardized health 

economic parameters are applied. Undiagnosed cancer deaths do account for some of the 

differences across the model results, but this does not account for all of the differences. Even 

when assumptions are standardized regarding undiagnosed cancer deaths and health 

economic parameters, there are still some differences that continue across the models.

To summarize, the cost per QALY gained by the current vaccination program is less than 

$35,000 and is cost-saving in the HPV-ADVISE model. In all of the models, adult vaccination is 

much less cost-effective than the current program. However, there are notable differences in the 

cost-effectiveness estimates across models. Uncertainties in HPV natural history and 

transmission dynamics preclude a precise estimate of the cost-effectiveness of vaccination of 

adults. However, the results are more consistent when standardizing health economic 

assumptions and assumptions regarding deaths due to undiagnosed cancer. In the context of 

the existing program, vaccinating adults over age 26 years would produce relatively small 

additional health benefits. The NNV to prevent one case of disease is approximately 40 times 

higher for adults through age 45 years than the current program for anogenital warts, CIN 2/3, 

and cancer.

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The cost per QALY gained by harmonization of catch-up vaccination through age 26 years 

versus the current program in the HPV-ADVISE model is $178,000 using faster progression and 

lower natural immunity assumptions. There is no significant gain in QALYs using slower 

progression and higher natural immunity assumptions. The results are not so favorable or 

unfavorable as to make a strong economic case for or against harmonization through age 26 

years. The cost per QALY gained by adult vaccination through age 30 years exceeds $300,000 

in 4 of the 5 available models and exceeds $800,000 in the median of the 50 parameter sets in 

the HPV-ADVISE model. The cost per QALY gained by adult vaccination through age 45 years 

exceeds $400,000 in 3 of the 5 available models and exceeds $1,400,000 in the median of the 

50 parameter sets in the HPV-ADVISE model.

Discussion Points

Dr. Elbasha (Merck Modeling Group) thanked Dr. Chesson and CDC for a thorough review of 

the Merck model. They reviewed several lengthy documents, including dense mathematical 

equations, and detailed results from many modeling scenarios during several rounds. They 

asked several important questions and provided feedback that helped and will continue to help 

in refining the model, its inputs, and its predictions. Merck will continue to refine the Merck 

model and its predictions, and will continue to conduct analyses to address natural history, 

health economics, and other important inputs. The model results are still different and do not 

align with the other models, which requires further investigation. The models align when 

evaluating the current program of vaccinating younger cohorts, but exhibit a wide variety of 

results when vaccinating older cohorts. The understanding of the differences in the models have 

improved, but what accounts for the major differences is still not fully understood. Because the 

models are simplifications of a complex reality, all models have limitations. Merck thinks it is 

important for all modelers to work together to fully understand what might be driving the major 

differences in model results. This would include sharing equations, inputs, and other technical 

details of the models and harmonizing critical assumptions and inputs. Merck welcomes any 

further input from the CDC team and any opportunity to work with other modeling groups, 

including participation in comparative modeling societies and face-to-face meetings. This would 

greatly help decision-makers not only in the US, but also in jurisdiction around the work to 

accurately assess the public health impact and the true economic value of expanding 

vaccination to 45 years of age.

Dr. Moore requested clarification from Dr. Chesson regarding whether the incremental 

difference in the new version of the NNV was among those currently not recommended or if it 

was across the whole cohort adding in the small number of men 22 through 26 years of age not 

currently recommended for routine catch-up.

Dr. Chesson clarified that it focuses on the benefits of vaccinating the men in this age group, but 

technically it looks at the additional number vaccinated when these men are included and the 

additional number of cases averted. These cases could be averted through herd effects of 

vaccinating these men, but it is based on the benefits of extending the vaccination to include 

these men.

Dr. Hunter inquired as to whether Dr. Quach could comment on the 9vHPV vaccine being 

indicated up to age 45 in Canada, and whether the Canadian National Advisory Committee on 

Immunization (NACI) deliberated on this decision. In addition, he wondered whether different 

provinces had different approaches.

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Dr. Quach (NACI Canada) replied that this recommendation was made a while back not looking 

at the cost-effectiveness. They did not delve into other details such as Dr. Chesson described. It 

was more of a permissive indication than a solely publicly funded program. The provinces do 

employ different approaches. For example, Quebec is moving completely toward a mixed 

schedule and not providing public coverage up to even 26 years of age. Quebec’s program is 

based on 4th graders and teenagers. There is not a publicly funded program in Quebec or most 

of the other provinces.

Dr. Stephens requested clarity on the undiagnosed cancers in two of the models in terms of 

where those data originated, as they did not appear to be real.

Dr. Chesson clarified that the estimates of deaths due to undiagnosed cancers were outputs of 

the model. They are not inputs into the model based on a specific data source. He requested 

that a representative from the Merck Modeling Group explain how they arrived at these 

estimates in their model.

Dr. Elbasha (Merck Modeling Group) indicated that death is an outcome in all of the models. It 

depends on assumptions regarding the natural history as well as many factors in the inputs on 

transmission, progression, diagnosis, and prevention efforts. When they calibrated the Merck 

model, meaning that they included certain inputs to match outcome data, they match to agespecific and HPV type-specific prevalence. They matched the data on cervical cancer incidence 

by age from the registry. Then they started looking at the overall number of deaths that occurred 

among vaccinated and unvaccinated. As Dr. Chesson mentioned, the registries capture all 

deaths if someone is diagnosed. However, registries by definition include only individuals who 

are diagnosed with cancer. The Merck model also accounts for the fact that someone can be 

dying from cancer but not be diagnosed. Merck is looking at data for more cancer mortality 

statistics to make sure that by matching inputs in the model, they match overall deaths from 

cancer whether it is diagnosed or not because they think that deaths can occur from 

undiagnosed cancer. 

Evidence to Recommendations (EtR) Framework

Elissa Meites, MD, MPH

Medical Epidemiologist, Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Meites presented two EtR summaries, one for each policy question. First, the EtR for 

Harmonization of Catch-Up HPV Vaccination through age 26 years. As a reminder, the 

elements of the ACIP EtR framework are the PICO (Population, Intervention, Comparison, 

Outcomes) Question and Background, Problem, Benefits & Harms, Values, Acceptability, 

Resource Use, Feasibility, and Balance of Consequences; the WG discusses each of these 

before arriving at a policy option for ACIP consideration. For each criterion, the WG summarized 

the evidence and considerations and offered the judgments of the HPV Vaccines WG.

The first PICO question was, “Should catch-up HPV vaccination be recommended for primary 

prevention of HPV infection and HPV-related disease for all persons through age 26 years?”

The population is males age 22 through 26 years since that is the group for whom the 

recommendations would change. The intervention is catch-up vaccination with 3 doses of HPV 

vaccine. The comparison is existing HPV vaccination recommendations. The outcome is 

primary prevention of HPV infection and HPV-related disease. 

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Regarding background, ACIP routinely recommends HPV vaccination for adolescents at age 11 

or 12 years. “Catch-up” vaccination recommendations apply to people who were not vaccinated 

at the routine age. Since 2006, ACIP has recommended vaccination for females at the routine 

age of 11 or 12 years, and catch-up vaccination for females through age 26 years. In 2011, 

ACIP added routine recommendations for males at age 11 or 12 years, with catch-up 

vaccination through age 21 years. Also, catch-up vaccination has been recommended through 

age 26 years for MSM (including men who identify as gay, bisexual, or who intend to have sex 

with men), for transgender persons, and for persons with certain immunocompromising 

conditions such as HIV. HPV vaccination coverage has been increasing among US 

adolescents, but remains low among young adults, and coverage in males is lower than 

coverage in females. In 2017, at-least-one-dose coverage among 13-17 year-olds was 69% in 

females and 63% in males. For 22-26 year-olds, it was 51% in females and 15% in males

[Walker TY, et al. MMWR. 2018;67(33):909-917, and https://www.cdc.gov/nchs/nhis/index.htm].

Regarding the problem, HPV is common in both women and men and causes over 33,000 

cancers annually in the US, including over 20,000 cancers in women and over 13,000 cancers 

in men. The existing HPV vaccination program for US adolescents has the potential to prevent 

the majority of these cancers. However, it is uncertain how much HPV-related morbidity and 

mortality is related to new HPV infections acquired by men at ages 22 through 26 years. The 

WG feels that that HPV-related disease is a problem of public health importance, and that 

preventing new HPV infections among 22-through-26 year-old males is probably of public health 

importance.

Regarding desirable anticipated effects (benefits), efficacy has been demonstrated in this age 

group. Clinical trials have shown that HPV vaccines are effective against infection and related 

disease due to HPV types that recipients are not infected with at the time of vaccination. The 

additional benefit of vaccinating males in this age range would be small compared with the 

benefit of the existing program. The NNV to prevent one case of anogenital warts, CIN 2+, or 

cancer is 9, 22, and 202, respectively, under the existing program. For expanding 

recommendations for males through age 26 years to harmonize catch-up vaccination across 

genders, the NNV would be 40, 450, and 3260, respectively, in a subset of analyses in the HPVADVISE model with more favorable model assumptions for adult vaccination.

As for undesirable anticipated effects (harms), in 9vHPV clinical trials, there were no serious 

vaccine-related events among males aged 9-26 years. AEs were generally less common among 

males than among females. HPV vaccines have an excellent safety profile based on large 

clinical trials and post-licensure effectiveness data. Over 100 million doses of HPV vaccine have 

been given in the US. The additional benefit of vaccinating males in this age range would be 

small compared to the existing program. However, small desirable effects outweigh minimal 

undesirable effects of HPV vaccination. Thus, the judgment of the WG is that this favors 

intervention. 

Full grading of recommendations, assessment, development, and evaluation (GRADE) for use 

of 4vHPV and 9vHPV in males have been publicly available since these ACIP recommendations 

were made in 2011 and 2015, respectively. For males through age 26 years, GRADE evidence 

level, or certainty of the evidence, is 2 (moderate) for benefits of 4vHPV and 3 (low) for benefits 

of 9vHPV, and 2 (moderate) for safety of 4vHPV and 2 (moderate) for safety of 9vHPV [GRADE 

for HPV Vaccine for Males [https://www.cdc.gov/vaccines/acip/recs/grade/hpv-vac-males.html. 

Linked from MMWR; December 23, 2011 / 60(50);1705-8; GRADE for Use of 9vHPV in 

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Females and Males. https://www.cdc.gov/vaccines/acip/recs/grade/hpv-9v.html. Linked from 

MMWR; March 27, 2015 / 64(11);300-304]. 

Regarding values and acceptability to the target population, a systematic review of 22 published 

studies found that the overall mean acceptability of HPV vaccine was moderate at 57 on a 100-

point scale. In the 9 studies reporting sexual orientation, there was no significant difference in 

acceptability between gay, bisexual, or other MSM and heterosexual men. In terms of whether 

the target population feels that the desirable effects are large relative to undesirable effects, the 

judgment of the WG is “probably yes.” As for whether there is important uncertainty about or 

variability in how much people value the main outcomes, the judgment is “No Important 

Uncertainty or Variability.” 

Next the WG considered acceptability to key stakeholders, including programs and vaccine 

providers. In a 2018 survey conducted by AIM, 51 immunization programs responded and 50 

(98%) were in favor of harmonizing the recommended age for catch-up vaccination to include 

everyone through age 26 years. Reasons the majority of programs favored harmonization were: 



























Easier to implement (92%)

Easier to explain to patients (88%)

Will simplify health department recommendations and guidelines (84%)

Easier to explain to providers (84%)

Facilitate reaching high-risk populations (84%)

To create equity between genders (78%)

Reduce the burden on health care providers (76%)

In a 2018 survey of primary care physicians (pediatricians, family physicians, and internal 

medicine physicians), 93% were in favor of a change to harmonize the recommended age for 

catch-up vaccination to include everyone through age 26 years, and 27% agreed that current 

catch-up recommendations with different upper ages for males and females have caused 

challenges or confusion. Reasons the majority (n=713) of physicians favored harmonization 

included: 

Simplify the vaccination schedule (99%)

Easier to implement (97%)

Easier to explain to patients (96%)

Facilitate reaching high-risk populations (88%)

Reduce burden on health care providers (80%)

Create equity between genders (61%)

The judgment of the WG is that yes, the intervention is acceptable to key stakeholders.

Regarding resource use, health economic analyses were conducted. In the context of the 

existing program for adolescents and catch-up, the incremental cost per QALY gained for 

expanding male vaccination through age 26 years was $178,000 in a subset of analyses in the 

HPV-ADVISE model with more favorable model assumptions for adult vaccination. Although 

less cost-efficient, absolute costs of vaccination would likely increase by less than 5% in the 

long-term under the expanded recommendation. These results are not so favorable or 

unfavorable as to make a strong economic case for or against harmonization through age 26 

years. As for whether the option is a reasonable and efficient allocation of resources, the 

judgment of the WG is that this is uncertain.

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Regarding feasibility, this intervention is a simplifying modification to an existing vaccination 

program and is considered feasible to implement. ACIP already recommends catch-up HPV 

vaccination for some people aged 22 through 26 years, including those who are female and 

certain special populations. A simplified adult immunization schedule is expected to be easier to 

explain and to remember [Meites E, Kempe A, Markowitz LE. Use of a 2-dose schedule for HPV 

vaccination—Updated recommendations of the ACIP. MMWR. 2016;65:1405–1408]. The 

judgment of the WG is that this option is feasible to implement.

After weighing the evidence, the judgment of the WG about the overall balance of

consequences is that desirable consequences probably outweigh undesirable consequences in 

most settings. The WG feels there is sufficient information to move forward with a 

recommendation at this time. Based on the evidence and considerations discussed, the policy 

option for consideration is to recommend the intervention. The next presenter, Dr. Markowitz, 

will offer the proposed recommendation text. 

In the second half of this presentation, Dr. Meites presented the EtR for HPV vaccination of 

adults older than age 26 years. The WG’s second PICO question was, “Should catch-up HPV 

vaccination be recommended for primary prevention of HPV infection and HPV-related disease 

for all persons ages 27 through 45 years?” The population is persons age 27-45 years, the 

intervention is catch-up vaccination with 3 doses of HPV vaccine. The comparison is persons 

age 27-45 years with no catch-up HPV vaccination. The outcome is primary prevention of HPV 

infection and HPV-related disease. 

Regarding background, HPV is a commonly sexually transmitted infection. Persistent HPV 

infections can develop into cancers, usually several decades later. Vaccination against HPV is 

recommended to prevent new HPV infections and subsequent disease. In October 2018, based 

on results from quadrivalent vaccine clinical trials in women through age 45 years and bridging 

immunogenicity and safety data in women and men, the FDA approved 9vHPV for use in US 

women and men through age 45 years [Food and Drug Administration. Prescribing information 

[package insert]. Gardasil 9 [human papillomavirus 9-valent vaccine, recombinant] Silver Spring, 

MD: US Department of Health and Human Services, Food and Drug Administration; 2018]. 

Regarding the problem, over 33,000 cancers are caused by HPV annually in the US, including 

cervical, vaginal, vulvar, penile, anal, and oropharyngeal cancers. Again, the existing HPV 

vaccination program for US adolescents has the potential to prevent the majority of these 

cancers. It is uncertain how much HPV-related morbidity and mortality are related to new HPV 

infections acquired at ages 27 through 45 years [https://www.cdc.gov/cancer/hpv/statistics, and 

Saraiya M, et al. U.S. assessment of HPV types in cancers: implications for current and 9-valent 

HPV vaccines. J Natl Cancer Inst. 2015 Apr 29;107(6):djv086]. The mean age of acquisition of 

causal HPV infection for cancers is unknown, but estimated to be decades before cancer is 

diagnosed. [Schiffman M, et al. Carcinogenic human papillomavirus infection. Nat Rev Dis 

Primers. 2016 Dec 1;2:16086] HPV incidence is highest among people in the age range of 

teens to early 20s. First HPV infections are acquired soon after first sexual activity, so most 

sexually active adults have been exposed to HPV already. Nevertheless, at any age, having a 

new sex partner is a risk factor for acquiring new HPV infections. Exposure to HPV decreases 

among older age groups, as the percentage of people reporting a new sex partner within the 

past year is lower in older age groups than among younger age groups. [Winer RL, et al. 

Incident Detection of High-Risk HPV in a Cohort of High-Risk Women Aged 25-65 Years. J 

Infect Dis. 2016 Sep 1;214(5):665-75.] The existing US HPV vaccination program has resulted 

in significant declines in prevalence of vaccine-type HPV infections, anogenital warts, and 

cervical precancers. Declines have been observed among both vaccinated and unvaccinated 

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persons, suggesting protective herd effects [Markowitz LE, et al. Ten Years of Human 

Papillomavirus Vaccination in the United States. Academic Pediatrics. 2018]. Based on the most 

recent national data on prevalence of HPV infections under the existing vaccination program, 

compared to the pre-vaccine era, 2013-2016 prevalence of quadrivalent vaccine-type HPV 

infection declined 86% (from 11.5 to 1.8%) among 14-19 year-olds and declined 71% (from 18.5 

to 5.3%) among 20-24 year-olds. Declines seen in older age groups were not significant, but 

over time, further declines are anticipated in the older age groups as vaccinated women age 

into these groups [McClung NM, et al. HPV prevalence among females in the United States, 

NHANES. 68th EIS Conference; April 2019; Atlanta, GA]. The WG agrees that HPV-related 

disease is a problem of public health importance. However, the amount of HPV-related disease 

that could be prevented by vaccinating 27-45 year-olds is small, compared with the amount of 

disease that can be prevented by vaccinating at younger ages. Preventing new HPV infections 

among 27-45 year-olds is of uncertain public health importance.

Regarding desirable anticipated effects (benefits), clinical trials have shown that HPV vaccines 

are effective against infection and related disease due to HPV types that recipients are not 

infected with at the time of vaccination. In the FUTURE III trial of quadrivalent vaccine in adult 

women, against a combined endpoint of persistent HPV infection, extragenital lesions, and/or 

CIN 1+, per-protocol efficacy was 88.7% with a confidence interval of 78% to 95%. Intention-totreat (ITT) results were lower, since these included women with previous HPV exposures and 

prevalent HPV infections at baseline even before they were vaccinated. The ITT efficacy was 

47.2% with a confidence interval of 33% to 58%. In the 9vHPV trial presented earlier in this 

session, antibody titers were non-inferior in women age 27-45 years compared to women age 

16-26 years. Over 99% of women in both groups seroconverted to all 9-valent vaccine types

[Castellsagué X, et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV 

(types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. British Journal of 

Cancer. 2011;105:28-37; Luxembourg A. 9vHPV immunogenicity and safety trial in mid-adult 

females. Presentation to ACIP, Atlanta, GA. June 2019]. Desirable anticipated effects vary. HPV 

vaccines are most effective when given before exposure to any HPV. The population benefit of 

adult vaccination would be minimal in the context of the existing program, yet some individuals 

in this age range might be able to benefit from vaccination. Recall that under the existing 

program, the NNV to prevent one case of anogenital warts, CIN 2+, or cancer, is 9, 22, and 202, 

respectively. For expanding vaccination to include adults through age 45 years, the NNV would 

be substantially higher at 120, 800, and 6500, respectively, according to a subset of analyses in 

the HPV-ADVISE model with more favorable model assumptions for adult vaccination

[Castellsagué X, et al. End-of-study safety, immunogenicity, and efficacy of quadrivalent HPV 

(types 6, 11, 16, 18) recombinant vaccine in adult women 24-45 years of age. British Journal of 

Cancer. 2011;105:28-37; NNV results from HPV-ADVISE, per Chesson HW, Overview of Health

Economic Models for HPV Vaccination of Mid-Adults, presentation to ACIP, Atlanta, GA, June 

2019].

Regarding undesirable anticipated effects (harms), there is abundant evidence for safety of HPV 

vaccines. In 9 clinical trials of 9vHPV, 4vHPV, or 2vHPV vaccine in adults older than age 26 

years (n=14,057), there were few SAEs and no vaccine-related deaths [Meites E, GRADE for 

HPV Vaccination of Mid-Adults. ACIP, Atlanta, GA. October 2018; and 

http://www.cdc.gov/vaccines/acip/recs/grade/table-refs.html]. Yet from a public health 

perspective, some WG members felt that adult vaccination might detract from the adolescent 

vaccination program, which remains the main focus for HPV prevention. Unanticipated harms 

could occur if vaccination of previously exposed or ill adults were to cloud data on vaccine 

safety or efficacy, or if communication messages were to focus on sexual transmission rather 

than HPV disease prevention. 

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The judgment of the WG is that desirable anticipated effects vary. Compared with the benefit of 

the existing HPV vaccination program for adolescents and young adults through age 26 years, 

the additional population-level benefit of vaccinating people age 27 through 45 years would be 

minimal. Yet some individuals in this age range might be able to benefit from vaccination 

against HPV types they have not yet encountered. Undesirable anticipated effects are also 

minimal, given abundant evidence for safety of HPV vaccines. The WG acknowledges that there 

could be concerns about potential undesirable unanticipated effects on the program as well. As 

for whether the desirable anticipated effects outweigh the undesirable anticipated effects, the 

judgment of the WG is that this is unclear.

Full GRADE tables with detailed assessment of the certainty of the evidence were presented to 

ACIP in October 2018. The only change is that the WG is adding the new results from the 

9vHPV observational trial that was presented during this session. Therefore, the number of 

studies has increased by one for immunogenicity and safety, but the overall certainty of the 

evidence has not changed. The certainty of the evidence on benefits, based on 3 RCTs of 

4vHPV or 2vHPV efficacy and immunogenicity and 6 observational trials of immunogenicity, 

was GRADE evidence level 2 (moderate quality evidence). The certainty of the evidence on 

harms, based on 5 RCTs and 4 observational trials, was also GRADE evidence level 2 

(moderate quality evidence). The certainty of the evidence was level 2 or moderate for both 

effectiveness and safety of the intervention. Note that the evidence presented in the GRADE 

tables has to do with individual-level outcomes on vaccine safety and effectiveness; outcomes 

in GRADE do not speak to population-level outcomes or any programmatic concerns [Meites E, 

GRADE for HPV Vaccination of Mid-Adults. ACIP, Atlanta, GA. October 2018; and 

http://www.cdc.gov/vaccines/ acip/recs/grade/table-refs.html].

Regarding values and acceptability to the target population, in 9 published studies of adults, 

acceptability varied across studies, yet overall was moderate to high. Acceptability was higher 

when vaccine was assumed to be free and/or a health care provider made a recommendation.

Acceptability varied by study population and methodology. Regarding whether the target 

population feels that the desirable effects are large relative to undesirable effects, the judgment 

of the WG is “probably yes.” As for whether there is important uncertainty about or variability in 

how much people value the main outcomes, the judgment of the WG is that there is possibly 

important uncertainty or variability.

For acceptability to key stakeholders, the WG notes that there are no recently published data 

assessing US stakeholder acceptability of routine HPV vaccination among 27 through 45 yearolds. However, vaccines for other conditions are routinely given to adults in this age range. In a 

2019 survey about HPV vaccination recommendations based on shared clinical decisionmaking for individuals, among 45 immunization programs, the majority (27 programs, or 60%) 

anticipated that it would be either very challenging or somewhat challenging for immunization 

programs to communicate a recommendation for clinical decision-making to vaccine providers 

in their jurisdiction. Another 16 programs (36%) said it would be not challenging. Almost half (19 

programs, or 42%) thought it would be either easy or somewhat easy for vaccine providers to 

determine patients in this age group who might benefit from vaccination, while another 19 

programs (42%) said it would be not easy. Most (31 programs, or 69%) anticipated challenges 

to implementing such a recommendation. [Association of Immunization Managers (AIM) survey, 

January-February 2019]. It is uncertain whether this amounts to an option acceptable to key 

stakeholders.

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Regarding resource use, five health economic models of HPV vaccination in the US were 

reviewed. In these models, the cost-effectiveness ratio for the current HPV vaccination program 

ranged from cost-saving to about $35,000 per QALY gained. In the context of the existing 

program, expanding vaccination to adults through age 45 years would produce relatively small 

additional health benefits and less favorable cost-effectiveness ratios. For example, the 

incremental cost per QALY for also vaccinating adults through age 30 years exceeded $300,000 

in 4 of the 5 models. Variation in results across models was due to factors such as uncertainties 

about HPV natural history, as presented earlier in this session [Chesson HW. Overview of 

Health Economic Models for HPV Vaccination of Mid-Adults. Presentation to ACIP, Atlanta, GA. 

June 2019]. 

Also regarding resource use, globally, there is an HPV vaccine shortage as production capacity 

is not adequate to meet demand currently. The demand/supply imbalance is expected to last for 

the next 3 to 5 years. In some countries, including those with Gavi and UNICEF support, 

national introductions and multi-age cohort vaccination are unable to proceed due to lack of 

vaccine availability. Although no domestic vaccine shortage is anticipated, some WG members 

had serious concerns about HPV vaccination recommendations being extended to 27 through

45 year-olds in the US in this context. As for whether this option is a reasonable and efficient 

allocation of resources, the judgment of the WG was probably not.

Regarding feasibility, delivering any adult vaccination can be challenging in the US. Programs 

and funding for adult vaccination are not available in all jurisdictions, and adult immunization is 

performed primarily in the private sector. For shared clinical decision-making, identifying 

individuals likely to benefit from adult HPV vaccination could be challenging. Some vaccine 

providers do not regularly assess sexual behaviors. However, in a 2015 survey of obstetriciangynecologists, 81% reported that they already stock and administer HPV vaccine [O’Leary et al. 

Vaccination Practices among Obstetrician/ Gynecologists for Non-Pregnant Patients. Am J Prev 

Med 2019]. Regarding health disparities and equity concerns, in general, it is not clear whether 

any recommendation for HPV vaccination in this age range would lead to greater uptake among 

individuals who are likely versus unlikely to benefit. Some WG members felt that recommending 

vaccination in this age range might reduce health disparities by increasing access to vaccination 

among adults with health insurance coverage. On the other hand, other WG members felt that 

recommending vaccination in this age range might enhance health disparities, as underinsured 

adults would be less likely to have access to vaccination since states have limited funds for 

adult vaccination programs. The overall judgment of the WG is that shared clinical decisionmaking for adult vaccination is probably feasible to implement, although there were a number of 

uncertainties about the potential consequences.

After weighing the evidence, the judgment of the WG is that the overall balance between 

desirable and undesirable consequences is closely balanced or uncertain. Taking into account 

ACIP’s role in providing timely guidance for vaccines with an indication from FDA, the WG 

would like to move forward with a recommendation. The HPV Vaccines WG was unanimous 

that HPV vaccination should not be routinely recommended for 27 through 45-year-olds. A 

majority felt that ACIP should recommend the intervention for individuals based on shared 

clinical decision-making, while a large minority felt that ACIP should not recommend the 

intervention in this age range. Thus, two policy options for this question are presented to ACIP 

for consideration. In the next presentation, Dr. Markowitz will offer the proposed 

recommendation text. 

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Lauri Markowitz, MD

Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

During this session, Dr. Markowitz reviewed the proposed recommendation text for the policy 

options to be voted on by ACIP. As heard from Dr. Meites, there was consensus on the WG for 

the first policy issue regarding harmonization of catchup through age 26 years. The WG 

consensus is “recommend the intervention.” This is the current text for routine and catch up 

vaccination: 

• “ACIP recommends routine HPV vaccination at age 11 or 12 years; vaccination can be 

given starting at age 9 years.” 

• “ACIP also recommends vaccination for females through age 26 years and for males 

through age 21 years who were not adequately vaccinated previously. Males aged 22 

through 26 years may be vaccinated. (See also: Special populations, Medical 

conditions).” 

The proposed recommendation text would not change the routine recommendation, and would 

simplify catch-up recommendations to read:

• “ACIP also recommends catch-up vaccination for persons through age 26 years who are 

not adequately vaccinated.”

Due to the limited length of the Policy Notes, there will be several footnotes in the proposed 

Policy Note referring to past recommendations. Specifically for the above statement, there will 

be a footnote stating the definition of adequately vaccinated: 

• “Definitions of persons considered adequately vaccinated are unchanged from the prior 

recommendation.” 

This is the footnote that will refer to text from 2016 policy that states:

• “Persons who initiated vaccination with 9vHPV, 4vHPV, or 2vHPV before their 15th 

birthday, and received 2 doses of any HPV vaccine at the recommended dosing 

schedule (0, 6–12 months), or 3 doses of any HPV vaccine at the recommended dosing 

schedule (0, 1–2, 6 months), are considered adequately vaccinated.” 

• “Persons who initiated vaccination with 9vHPV, 4vHPV, or 2vHPV on or after their 15th 

birthday, and received 3 doses of any HPV vaccine at the recommended dosing 

schedule, are considered adequately vaccinated.” 

Text in other sections would be impacted by the proposed harmonization text. In “Special 

Populations,” there is current text for MSM and for transgender persons stating 

recommendations for vaccination through age 26 years. The proposed harmonization text would 

replace the current text, which would no longer be needed:

• “For men who have sex with men, ACIP recommends routine HPV vaccination as for all 

males, and vaccination through age 26 years for those who were not adequately 

vaccinated previously.

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• For transgender persons, ACIP recommends routine HPV vaccination as for all 

adolescents, and vaccination through age 26 years for those who were not adequately 

vaccinated previously.”

Similarly, for medical conditions, the current text about catch up through age 26 years for 

persons with immunocompromising conditions would no longer be needed: 

• “ACIP recommends vaccination with 3 doses of HPV vaccine (0, 1–2, 6 months) for 

females and males aged 9 through 26 years with primary or secondary 

immunocompromising conditions...” 

For simplicity, the WG proposed a combined section header and one sentence for special 

populations and medical conditions reading: 

• Special Populations and Medical Conditions 

“The above recommendations for routine and catch-up age groups and for individuals 

older than the catch-up age group also apply to MSM, transgender people, and people 

with immunocompromising conditions.”

For the second policy issue regarding vaccination of adults older than age 26 years, two options 

were proposed by the WG: 1) recommend shared clinical decision-making (the majority 

opinion); or 2) do not recommend the intervention (the large minority opinion). The proposed 

recommendation text options were:

1) Shared clinical decision-making (majority opinion) option, which will include a footnote 

defining adequately vaccinated: 

• “ACIP recommends HPV vaccination based on shared clinical decision making for 

individuals ages 27 through 45 years who are not adequately vaccinated. HPV vaccines 

are not licensed for use in adults older than age 45 years.” 

2) Do not recommend the intervention (minority opinion) option:

• “ACIP does not recommend HPV vaccination for adults older than age 26 years.” 

In discussions in the WG, some members who favored shared clinical decision-making also 

mentioned these factors as contributing to why they favor the first option (“shared clinical 

decision-making”): 













There are some people in this age range who could benefit from vaccination 

Public health messages and guidance can be provided 

Clinicians faced with individual patient requests may do clinical decision-making anyway

Health insurance coverage for vaccination might reduce health disparities

Communicating who might benefit from vaccination will be fundamentally different for this 

age range; it is easier for clinicians to discuss sexual risk behaviors with adults than with 

adolescents 

This type of recommendation from ACIP would allow flexibility 

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However, some people felt that recommending vaccination in this age range might enhance 

disparities and equity concerns, as underinsured adults would be less likely to have access to 

vaccination since states have limited funds for adult vaccination programs. In discussions on the 

WG, some members mentioned these factors as contributing why they favor the second option 

(“Do not recommend”): 































Little public health benefit is expected from vaccinating people in this age range

Better stewardship of resources 

Adult vaccination might detract from the adolescent vaccination program which is the main 

focus of the vaccination program

Communicating who might benefit from vaccination in this age range would emphasize 

sexual behavior instead of HPV disease prevention, which is not consistent with messaging 

for adolescents

Shared clinical decision making is programmatically difficult 

Concern about equitable use of vaccine given the global vaccine shortage

The WG acknowledged the challenges of shared clinical decision-making. Considerations 

drafted for a Policy Note if there is a recommendation for shared clinical decision-making could 

include: 

HPV is a very common sexually transmitted infection. Although new HPV infections are most 

commonly acquired in adolescence and young adulthood, some adults are at risk for 

acquiring a new HPV infection. 

Ideally, vaccination should be given in early adolescence. Vaccination before exposure to 

HPV through sexual activity will result in the greatest efficacy. 

Vaccine efficacy is high among people who have not been exposed to HPV. 

Vaccine efficacy is lower among people previously exposed to vaccine-type HPV, likely 

including adults who are considered to be at high risk for HPV-related disease given multiple 

lifetime sex partners and/or certain immunocompromising conditions.

Most sexually active adults have already been exposed to some types of HPV, although not 

necessarily all of the HPV types targeted by vaccination.

At any age, having a new sex partner is a risk factor for acquiring a new HPV infection.

No clinical antibody test can determine whether a person is already immune or still 

susceptible to any given HPV type.

People who are in a long-term, mutually monogamous sexual partnership are not likely to 

acquire a new HPV infection.

HPV vaccines are prophylactic (i.e., they prevent new HPV infections) and do not prevent 

progression of HPV infection to disease, decrease time to clearance of HPV infection, or 

treat HPV-related disease.

The WG will continue to review data on vaccine efficacy and effectiveness in special 

populations, additional modeling results, post-licensure safety, and population impact and 

effectiveness of vaccination. 

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The proposed recommendation options for ACIP discussion and vote:

Vote #1:

Routine and Catch-Up Age Groups 

“ACIP recommends routine HPV vaccination at age 11 or 12 years; vaccination can be given 

starting at age 9 years. ACIP also recommends catch-up vaccination for persons through age 

26 years who are not adequately vaccinated.”

Vote #2:

Shared Clinical Decision-Making Option

“ACIP recommends HPV vaccination based on shared clinical decision making for individuals 

ages 27 through 45 years who are not adequately vaccinated. HPV vaccines are not licensed 

for use in adults older than age 45 years.”

Do Not Recommend the Intervention Option

“ACIP does not recommend HPV vaccination for adults older than age 26 years.” 

Discussion Points

Dr. Moore indicated that she shared the WG’s position regarding harmonization of the schedule 

through 26 years of age. While she recognized that there are individuals older than 26 years of 

age who could benefit from this vaccine and that there is not a current shortage domestically, 

the potential expansion of this recommendation to include millions more Americans gave her 

great pause in terms of the supply question. She would not want to do anything that would 

compromise the supply for the pre-teen and adolescent priority populations. She inquired as to 

whether they should consider deferring the age 27 through 45 years question and remain silent 

for a few years until supplies have stabilized, and they can be more confident that the decisions 

about this age group will not adversely affect access among priority populations where great 

benefit already has been demonstrated.

Dr. Markowitz replied that the WG heard a presentation from the manufacturer because of 

similar concerns. She invited a Merck representative to comment.

Rick Haupt (Global Medical Affairs, Merck) said he thought it was important to talk about the 

global supply in the context of the discussion during the morning. Merck recognizes that there is 

an imbalance globally in the demand and supply for GARDASIL®9, which they take very 

seriously. As Dr. Markowitz mentioned earlier, HPV vaccine recommendation goals have 

changed quite dramatically in the last few years. There have been new indications and 

recommendations for expanded use of the vaccine in many countries around the world, which 

has created an unprecedented demand on the GARDASIL®9 supply. As part of Merck’s global 

commitment to support global public health, they are making substantial investments to improve 

that supply. It will take a few years to manage that, but in the short-term they are working with 

countries around the world to try to provide vaccine adequately and equitably across both highand low-resource settings. As it pertains to the US, Merck fully anticipated the recommendations 

being discussed during this session in terms of the harmonization through 26 years of age and 

potential recommendations for shared clinical decision-making for those 27 through 45 years of 

age and have the supply to be able to manage those recommendations if voted on during this 

session. It is important to note, particularly in the 27 through 45 year olds, there are individuals 

in that age group who remain susceptible to one or more of the HPV types that are in 

GARDASIL®9. Many individuals are at risk for new infections in this age group. A shared clinical 

decision-making recommendation would be the appropriate recommendation to allow 

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individuals the opportunity to have access to the vaccine so that they can be protected from 

HPV-related disease, including cancer.

Dr. Ezeanolue observed that when the FDA approves a vaccine, it gives clinicians the power as 

physicians to use shared decision-making. If that is the case, ACIP’s role is different from FDA’s 

role, and ACIP should consider all of the other things that are of public health importance. From 

what he was hearing based on the presentations was that there is little public health importance 

in expanding the HPV vaccine recommendation to 27 through 45 year olds. He wondered what 

the policy implication would be if ACIP recommended shared decision-making, which seems 

already to be possible for physician with the FDA approval except for the issue of who pays for 

the vaccine. If ACIP does not make the recommendation, clinicians will still be able to use 

shared decision-making, but it would not be paid for. He just wanted to ensure whether this 

interpretation of the difference was correct. Dr. Markowitz confirmed that this was basically a 

correct interpretation. If a vaccine is licensed by the FDA, an individual can have a discussion 

with a provider and make a decision about whether they want the vaccine. If it did not have an 

ACIP recommendation for even shared clinical decision-making, her understanding was that it 

would not be covered by insurance.

Dr. Messonnier emphasized that this is complicated; they needed to step back to think about 

this in the context of all of the clinical decisions that are shared between a clinician and a 

patient. She thought the problem with ACIP remaining silent would be that among certain 

cadres of clinicians, it would be interpreted that basically ACIP thinks there should not be a 

conversation.

Dr. Cohn added that an ACIP recommendation for shared clinical decision-making would be 

reflected on the Adult Immunization Schedule; whereas, it would not be reflected there if ACIP 

stayed silent. Being on the schedule alerts providers and raises their awareness that they need 

to bring this to their patients to discuss.

Dr. Romero added that this also is an issue of equity in terms of the cost of the vaccine and who 

will have access.

Dr. Bernstein asked whether they knew how many individuals 27 through 45 years of age have 

commercial insurance and how many would have to self-pay to get the vaccine.

Dr. Markowitz reminded ACIP members that not everyone on the WG felt that clinical decisionmaking would lead to equity. Because there is not a lot of funding for adult vaccination, for those 

who do not have insurance, it would not necessarily increase equity.

Dr. Ezeanolue said he understood the rationale for ACIP making a shared clinical decisionmaking recommendation, but he felt that then ACIP would never make a recommendation that 

is “do not recommend” because the default recommendation would always be shared decisionmaking. There is an uncertain public health importance to expand this particular 

recommendation. Based on that, he thought ACIP should say “do not recommend” based on the 

lack of public health importance, irrespective of payment issues. There is a science to evidencebased decision making, and here the science says that there is uncertain public health 

importance.

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Dr. Talbot did not foresee HPV vaccination being expanded to all women through 45 years of 

age. However, there are women at risk, perhaps those who are recently divorced or are getting 

married for the first time at 40 and have not been vaccinated who might be able to benefit from 

getting immunized. She did not want that opportunity only to be for wealthy women. It needs to 

be for all women. 

Dr. Atmar added that this vaccine is immunogenic and appears to be effective in the age group 

under consideration. There are many clinicians who look at the ACIP recommendations to 

determine what should be given to their patients. If ACIP votes for “do not recommend” rather 

than the default shared decision-making, that will have a significant impact, particularly for some 

patient groups who may have risk factors for new infections and are not protected but may well 

be susceptible and at risk. While he agreed that shared decision-making is the default for any 

licensed drug, the effect that ACIP has on practice throughout the US is substantial.

Dr. Szilagyi thought that within the WG, the vast majority think that a small number of men and 

women might benefit from this vaccine. He did not hear anybody in the WG talk about large 

numbers of people benefitting. The challenge regards how to identify high risk individuals. To 

him there are two groups of high risk individuals, those who were high risk for HPV when they 

were younger and are continuing to be very high risk for new infections or those who were not 

as high risk and now have a new sexual partner or for behavioral reasons now are high risk. 

Shared decision-making is done all of the time in the adult world and is standard of care. He 

personally is worried about equity issues, and to him the important thing would be to try to 

identify and then perhaps vaccinate the very small number of individuals who would benefit from 

vaccine and not vaccinate the vast majority of women and men 27 through 45 years of age. 

Guidance from ACIP that could follow a recommendation of shared decision-making could help 

that. He also thinks more research is needed to determine who the very high risk patients are.

Dr. Walter echoed that and said that if they do adopt a shared decision-making recommendation 

model, the guidance that will follow will be important for the individual provider in discussing 

issues of risk with their patients.

Dr. Frey agreed with the majority of what had been said. She pointed out that it is more likely 

that an insurance company would pay for vaccination if it was recommended by ACIP.

Dr. Lee said she thought she was hearing that with population-level considerations there is a 

“yes” or “no” vote, such as occurred with RotaShield®. It sounded to her like shared clinical 

decision-making was really about the individual and clinician decision, recognizing that there is 

benefit to certain people but that perfectly identifying every individual in a general 

recommendation is a challenge. This would allow them some flexibility to be able to protect 

those who they think are interested in protection and may be at higher risk, which only could be 

assessed in a conversational setting. That said, she specifically asked the WG whether they 

need to formally assess and evaluate the impact of any recommendation they make on 

disparities. That would be incredibly helpful, particularly as they move into the shared clinical 

decision-making world. These decisions are no longer as straightforward as a simple “yes” or 

“no.”

Dr. Wharton answered Dr. Bernstein’s earlier question by indicating that according to the 

Census Bureau data from 2017, approximately 15% of individuals 26 through 45 years of age 

are uninsured. Medicaid is probably considered insured, but the degree to which Medicaid 

would cover this is likely to vary by state.

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Dr. Szilagyi added the highest age at which young adults can be on parents’ insurance is 26 

years, so the issue of 27 through 45 does not involve that age group. Among those who have 

either private insurance or Medicaid, the majority have private insurance. 

Dr. Moore pointed out that they had not seen anything presented about what the potential 

economic issues would be in terms of shared clinical decision-making. They only heard 

estimates for a routine recommendation for this group. While she agreed with Drs. Szilagyi and 

Talbot that among men and women in this age group, there are a small proportion who would 

benefit, they have not seen what shared clinical decision-making guidance would look like and 

what that implies in terms of the proportion of the population in this age group who would fall 

under those categories. She would feel more comfortable voting to recommend a shared clinical 

decision-making if she knew what that guidance would look like and for which people in this 

population it would apply. Thus, her preference was to delay voting on that component until 

later.

Dr. Hunter stressed that they should be careful to avoid making recommendations that 

inadvertently emphasize vaccinating adults more than children for certain infections, often 

because the benefit is greater in the children and adolescents. He also expressed concern 

about the list of considerations for shared decision-making. While he thought they were quite 

good for general reflection in an academic setting, but they may be very difficult to implement in 

clinical practice.

Dr. Fryhofer (AMA) said that speaking as a practicing physician and as a member of the WG, as 

Dr. Markowitz indicated, this was a very difficult decision for this WG. There was a majority 

decision, but there also was a very strong minority decision. She thought Dr. Moore raised some 

very important points, and she was very impressed by the deliberations she had heard during 

this session. One of her great concerns as a practicing physician, as an internist who sees 

children and adults of all ages, is that there is only a certain amount of vaccine. It is known that 

this vaccine works best in children. She also was concerned about mixed messaging. Having 

seen what has happened in the public arena in the past when a recommendation is made and 

the shared decision-making items are not so clearly defined is that it may be expanded to 

people who do not necessarily need it, which is not a great use of resources. This is not an 

inexpensive vaccine. It is a wonderful vaccine and to her is one of the most important things 

ACIP has addressed. In fact, ACIP voted to give HPV vaccine during her first ACIP meeting. 

This is a very tough decision and the details of the shared clinical decision-making need to be 

made very clear. This is not needed for every patient 27 through 45 years of age.

Dr. Messonnier reminded everyone that there had been recent discussions during previous 

ACIP meetings about how the decisions CDC was asking them to make were becoming harder 

than in a previous generation of decisions. She thought the second issue fell into that category. 

CDC recognized that there were gaps in the information ACIP had and that this made it hard to 

make a decision. However, it was not like they would have answers to these questions in the 

short-term. She made the commitment that whatever decision ACIP made, CDC would make 

the appropriate research questions a priority. If ACIP decided not to recommend this right now, 

CDC would work hard to determine what groups potentially would benefit from additional 

vaccination and bring the issue back a couple of years from now. If they decided to approve the 

shared clinical decision-making, CDC could figure out how that would be implemented and what 

the implications would be in terms of who is getting the vaccine, whether it is exacerbating 

equity issues, if there are going to be supply issues, et cetera. Given that no additional data are 

anticipated in the next 6 months, CDC preferred that ACIP come to some type of consensus or 

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conclusion on the second issue with the understanding that like anything, they will continue to 

research the issue.

In terms of the comment about the considerations she showed and whether they would be 

helpful, Dr. Markowitz said the WG realized that those were not guidance and they changed the 

term from “guidance” to “considerations.” It is true that it is very difficult to identify patients who 

might benefit. She agreed that those descriptions needed to be further refined, and they do 

have plans to try to review efficacy and effectiveness in special populations and do some 

modeling to determine whether they can identify people who would benefit. In terms of what Dr. 

Fryhofer mentioned, she confirmed that there was much discussion within the WG. There was a 

strong minority opinion opposed to shared clinical decision-making because of the difficulty 

identifying people, among other reasons, and concerns that a recommendation for shared 

clinical decision making would give license to some groups to be more actively promoting the 

vaccine.

Dr. Middleman (SAHM) expressed appreciation for this conversation. With the potential vote for 

shared clinical decision-making, she thought it was very important to have very clear guidance. 

She was somewhat concerned about the use of gender identity as an identification of risk. 

Gender identity is distinct from sexual behaviors. If they did vote on shared clinical decisionmaking, she thought they should create guidance that is as specific as possible about behaviors 

rather than groupings of people.

Dr. Eckert (ACOG) assured the voting members that from ACOG’s perspective, they already 

have had extensive internal discussions about how they would try to provide guidance for 

shared clinical decision-making, knowing that many women in their patient population could 

benefit from this vaccine and at the same time knowing that not everybody in this age group 

needs this vaccine. She thought this would be a very active area and that ACOG would engage 

heavily in trying to assist its providers with guidance.

Dr. Rockwell (AAFP) said she felt like they were almost giving clinical and shared decisionmaking too much discussion and weight. In her clinical practice, she sees children and adults 

and has been doing so for over 25 years. She felt that it would not be difficult for her to 

recognize who might benefit from HPV vaccination, such as a newly divorced woman or a 28-

year old patient who has never had sex and is now getting married. Therefore, she did not think 

ACIP needed to be that explicit in these recommendations. It seemed that they were giving HPV 

more attention than it actually needed compared to other vaccination recommendations. In 

terms of the recommendations for boys or young men for shared clinical decision-making, they 

did not have this type of discussion.

Dr. Szilagyi said he agreed that it is much easier in the adult world to identify behaviors and 

internist and family physicians do this all of the time. It is much more difficult in the pediatric 

world to identify current behaviors or behaviors in the next year or two. He agreed that this is 

about identifying behaviors rather than demographic characteristics.

Dr. Ezeanolue said he thought HPV vaccine did require the attention that it was getting. He has 

family members who have died from this cancer.. He wants people to get the HPV vaccine 

when it is most efficient, most cost-effective, and when it is of public health importance. The 

idea was not about limiting people from getting HPV vaccine. It was actually about increasing 

the number of people getting HPV vaccine by focusing on the target group where they get the 

best “bang for the buck.” What he was challenging was that shared decision-making is different 

from focusing on target groups. The woman who gets divorced may have received the vaccine 

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at 16. The idea is that if someone already received the vaccine on time, it does not matter if they 

get divorced or have a new sex partner later. The idea is to get people to receive it on time in 

the first place. The challenge he has was that if ACIP made this decision today, he could not 

imagine any other scenario where ACIP would be able to say “no” to any vaccine. Once FDA 

approved it, they were saying this vaccine is safe for use in individuals. However, that is not the 

role of ACIP. It is the role of the FDA. Once FDA approves it, what goes through his mind as a 

clinician in practice is that he now has the shared clinical decision making background. He 

thought that scenarios when ACIP could say “no” is where there were other considerations for 

example, use of resources. Should we use the resources to target more HPV immunizations at 

age 10 to 26 years, where there will be a public health benefit, or should we use those 

resources to focus on an older age group where there is questionable public health importance?

Dr. Markowitz said the point Dr. Ezeanolue was making was exactly why no one on the WG 

favored a routine catch-up recommendation for adults through age 45 years, and also was one 

of the reasons some WG members had concerns about even shared clinical decision-making. 

These issues certainly entered into the decision about not extending routine catch-up through 

45 years of age.

Dr. Romero indicated that unless there were further comments, they needed a motion and 

second for each of the two recommendations to prepare for the vote following public comment.

Dr. Szilagyi made a motion, which Dr. Walter seconded, to approve the proposed 

recommendation text for harmonization reading:

Routine and Catch-Up Age Groups

“ACIP recommends routine HPV vaccination at age 11 or 12 years; vaccination can be 

given starting at age 9 years. 

ACIP also recommends catch-up vaccination for persons through age 26 years who are 

not adequately vaccinated.”

Dr. Frey made a motion, which Dr. Lee seconded, to approve the proposed recommendation 

text option for vaccination of adults older than age 26 years based on shared clinical decisionmaking reading:

“ACIP recommends HPV vaccination based on shared clinical decision-making for 

individuals ages 27 through 45 years who are not adequately vaccinated. HPV vaccines 

are not licensed for use in adults older than age 45 years.”

Dr. Hunter inquired as to whether he could make a motion instead that HPV vaccination for 

adults older than age 26 is not recommended.

Dr. Romero clarified that he could not, as they must vote on the first motion and then if 

necessary take up Dr. Hunter’s motion.

Dr. Hunter did not think this made sense logically. He objected to this pointing out that the order 

not to recommended HPV vaccination for adults older than age 26 would make more sense.

Dr. Cohn emphasized that the motion already had been placed on the table for shared clinical 

decision-making, following which another motion could be placed on the table if it did not pass. 

She clarified that they were making the motions for the votes and then staying the vote until the 

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afternoon sessions subsequent to the Public Comment period. The votes are included here for 

continuity.

Motion/Vote #1: Harmonization of Catch-Up Vaccination Through 26 Years 

Dr. Szilagyi made a motion to approve the proposed recommendation text for harmonization 

reading, Routine and catch-up age groups: “ACIP recommends routine HPV vaccination at age 

11 or 12 years; vaccination can be given starting at age 9 years. ACIP also recommends catchup vaccination for persons through age 26 years who are not adequately vaccinated.” Dr. Walter 

seconded the motion. No COIs were declared. The motion carried with 14 affirmative votes, 0 

negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A 

Prior to the vote pertaining to shared clinical decision-making, Dr. Markowitz shared the main 

discussion points made by WG members who favored “shared clinical decision-making” and 

those who favored “do not recommend.”

Discussion: WG Members Who Favored “Shared Clinical Decision-Making”

























There are some people in this age range who could benefit from vaccination 

Public health messages and guidance can be provided 

Clinicians faced with individual patient requests may do clinical decision-making anyway

Health insurance coverage for vaccination might reduce health disparities

Communicating who might benefit from vaccination will be fundamentally different for this 

age range; it is easier for clinicians to discuss sexual risk behaviors with adults than with 

adolescents 

This type of recommendation from ACIP would allow flexibility 

Discussion: WG Members Who Favored “Do Not Recommend”

Little public health benefit is expected from vaccinating people in this age range

Better stewardship of resources 

Adult vaccination might detract from the adolescent vaccination program which is the main 

focus of the vaccination program

Communicating who might benefit from vaccination in this age range would emphasize 

sexual behavior instead of HPV disease prevention, which is not consistent with messaging 

for adolescents

Shared clinical decision making is programmatically difficult 

Concern about equitable use of vaccine given the global vaccine shortage

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Motion/Vote #2: Shared Clinical Decision-Making

Dr. Frey made a motion to approve the proposed recommendation text option for vaccination of 

adults older than age 26 years based on shared clinical decision-making reading, “ACIP 

recommends HPV vaccination based on shared clinical decision-making for individuals ages 27 

through 45 years who are not adequately vaccinated. HPV vaccines are not licensed for use in 

adults older than age 45 years.” Dr. Lee seconded the motion. No COIs were declared. The 

motion carried with 10 affirmative votes, 4 negative votes, and 0 abstentions. The disposition of 

the vote was as follows:

10 Favored: Atmar, Ault, Frey, Lee, McNally, Romero, Stephens, Szilagyi, Talbot, Walter

 4 Opposed: Hunter, Moore, Ezeanolue, Bernstein

 0 Abstained: N/A

Discussion After HPV Votes 

Dr. Romero invited members to share their rationale for how they voted.

Dr. Ault noted that he is a new member of ACIP and the WG, and he thought Dr. Szilagyi

summarized what he was thinking earlier in the day when he said that they did not have a 

consensus for a broad recommendation, but there may be a few individuals in this age group 

who would benefit from vaccination.

Dr. Szilagyi emphasized that he voted “yes” because of what he said earlier about believing that 

the proportion of patients who would benefit is small but exists, high risk individuals can be 

identified, guidance following the vote would be very helpful for clinicians, and the majority of 

patients in this age group should not receive the vaccine.

Dr. Bernstein indicated that he voted “no” because he was concerned about potential 

disparities, difficulty in implementing this in clinical practice, concern about the vaccine supply in 

the US and worldwide, and lack of clarity regarding how this may negatively impact 

immunization rates of teenagers and young adults.

Dr. Ezeanolue said that he voted “no” because he supports HPV vaccine and does not want the 

focus to change and move away from the target audience where the vast majority of benefits 

occur, which is among those younger than 26 years of age. Considering that there already is a 

global shortage, diversion to a smaller group where there is little demonstrated effectiveness or 

public health value does not seem prudent. He was concerned that there is always a pressure 

on the imbalance between supply and need, and that the focus may be shifted away from 

millions of young girls in countries that may not be able to stock these vaccines because of a 

shifting focus. This runs the risk that some countries may delay administration of HPV vaccine. 

He supports HPV vaccine, but wants to reach the greatest majority of people who will benefit 

from it.

Dr. Stephens indicated that he voted “yes” because he thinks this is an effective and safe 

vaccine. He does believe that “shared clinical decision-making” in this case needs to be welldefined by the guidance, because this is an area in which there are certain situations where this 

vaccine could be effective.

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Dr. Moore said that she voted “no” because there were no details on the shared clinical 

decision-making, for whom they would be suggesting this vaccine would be appropriate, or what 

size of the population of men and women in that large age group would be suggested. In the 

absence of any information on the details of what that means and in the presence of supply 

questions, she did not feel comfortable expanding a recommendation to such a huge 

population. She also was concerned that despite assurances from the manufacturer, supply 

could become a problem that distracts from the priority recipients and she did not want to do 

anything to compromise that.

Dr. Hunter said he voted “no” because he was worried that this would send a negative message 

that vaccinating at a younger age is not as important and effective as it is. Because of that and 

because the guidance might not be as clear or effectively communicated by the public sector, 

the private sector may communicate this in a way that meets their best interests, and that 

clinicians may choose the easy way out based on their perception that most parents have a 

problem with this vaccine though the data show that that is not true.

Dr. Walter indicated that he voted “yes” to allow for shared clinical decision-making to allow 

those at risk to get the vaccine, but he does believe that additional guidance needs to be 

provided.

Dr. Frey said she voted “yes” because she appreciated the concern about perhaps missing 

earlier HPV vaccination at the recommended age range. The guidance included in the ACIP 

recommendation statement will provide support for the idea that young children should get 

vaccinated to prevent cancer and those who missed vaccinations would have the opportunity to 

receive the vaccine later.

Dr. Romero indicated that he voted “yes” for all of the reasons state previously. He observed 

that this is likely to be a frequent issue in the future that the ACIP will be dealing with as 

vaccines become more complex and more targeted for certain populations.

Introduction

Grace Lee, MD, MPH

Pneumococcal Vaccines WG Chair

Advisory Committee on Immunization Practices

Dr. Lee reminded everyone that the Pneumococcal Vaccines WG’s terms of reference are to: 1) 

Review current data on efficacy, effectiveness, immunogenicity, and cost-effectiveness of 

pneumococcal vaccines; 2) Review current recommendations considering up-to-date evidence, 

including epidemiological studies conducted post-licensure, and assess strength of the 

evidence; and 3) Revise or update recommendations for pneumococcal vaccine use, as 

needed. 

Pneumococcal Vaccines

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ACIP recommended pneumococcal conjugate vaccine (PCV)7 for children in 2000, followed by 

PCV13 in 2010 when that became available. In 2012-2013, ACIP recommended PCV13 for 

individuals with immunocompromising conditions. In 2014, ACIP recommended PCV13 in series 

with PPSV23 for adults ≥65 years of age. The WG is currently re-evaluating the use of PCV13 

in adults ≥65 years of age. When ACIP recommended PCV13 in series with PPSV23 for adults 

≥65 years of age in 2014, the rationale was that the recommendation was in the short-term

because there was still a significant burden of disease among older adults, particularly due to 

pneumococcal pneumonia. The long-term public health benefits at that time were expected to 

be limited since the indirect effects from the pediatric PCV13 use were expected to increase. 

Thus, the recommendation was made in 2014 with a commitment to re-evaluate this policy 4 

years later and revise it as needed. 

The policy question the WG has been examining is, “Should PCV13 be administered routinely to 

all immunocompetent adults aged ≥65 years in the context of indirect effects from pediatric PCV 

use experienced to date?” The population of interest is immunocompetent adults ≥65 years of 

age. The intervention is PCV13 in series with PPSV23 in the context of indirect effects. The 

comparison is PPSV23 alone in the context of indirect effects. The core outcomes are invasive 

pneumococcal disease (IPD), pneumonia, mortality, and safety. 

Again, the population covered by the policy question are immunocompetent adults ≥65 years of 

age. Not included in the current policy discussion are adults ≥19 years old with an 

immunocompromising condition, including:

Chronic renal failure 

Nephrotic syndrome 

Immunodeficiency 

Iatrogenic immunosuppression

HIV

Cochlear implants

CSF leaks

Generalized malignancy

Hodgkin disease

Leukemia or Lymphoma

Multiple myeloma

Solid organ transplants

Congenital or acquired asplenia

Sickle cell disease or other 

hemoglobinopathies

Adults ≥19 years old with one of the above immunocompromising condition are still 

recommended to receive PCV13 in series with PPSV23 based on ACIP’s 2012

recommendations.

The proposed policy options for a vote during this meeting:

A. ACIP recommends PCV13 for all adults ≥65 years who have not previously received 

PCV13. PCV13 should be given first, followed by a dose of PPSV23 (2014 recommendation 

as currently stated).

B. ACIP recommends PCV13 based on shared clinical decision-making for adults ≥65 years 

who do not have an immunocompromising condition and who have not previously received 

PCV13. All adults ≥65 years should receive a dose of PPSV23. 

C. ACIP no longer recommends PCV13 for adults ≥65 years who do not have an 

immunocompromising condition. All adults ≥65 years should receive a dose of PPSV23 (pre2014 policy).

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In terms of the WG rationale, the goal was to re-evaluate the 2014 policy to recommend PCV13 

in series with PPSV23 for adults ≥65 years. The WG began with this thinking about continuing 

the 2014 recommendation and thought that the answer should be “yes” or “no.” The WG 

proposed to focus on whether to continue the current recommendation as the goal of its reevaluation. Further discussions among the WG members revealed that “no” could mean two 

different things, shared clinical decision-making or no longer recommending. Dr. Lee expressed 

her hope that based on Dr. Matanock’s presentations and the discussion, ACIP would recognize 

the diversity among the WG members, who were split amongst the three options and there was 

no clear consensus as this is such a complex decision.

Dr. Lee indicated that during this session, presentations and discussion would focus on the 

following topics:

 Considerations for PCV13 use among adults 65 years and older and a summary of the EtR

 Proposed policy options 

 Feedback from liaison and ex-officio members on the policy options proposed

 Discussion about the considerations for PCV13 use among adults ≥65 years old

Considerations for PCV13 Use Among Adults ≥65 

Years Old and A Summary of the EtR Framework

Almea Matanock, MD, MS

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Matanock summarized the considerations for PCV13 use among adults ≥65 years of age, as 

well as the EtR Framework. In re-evaluating PCV13 use, the following key questions were 

considered:

 What indirect effects from pediatric PCV13 use were observed among adults aged ≥65 

years before 2014?

 What effects from PCV13 use have we observed among adults aged ≥65 years since 

2014? 

 What additional benefits are expected from continued PCV13 use among adults aged ≥65 

years given the remaining disease burden?

As a reminder, the population covered by the policy question are immunocompetent adults ≥65 

years of age. Not included in the current policy discussion are adults ≥19 years old with an 

immunocompromising condition as identified by Dr. Lee, who are recommended to receive 

PCV13 in series with PPSV23 per the 2012 ACIP policy. The 2012 policy is not part of the 

current re-evaluation.

In terms of the first key question regarding indirect effects, since PCV’s first introduction in 2000, 

there was a 9-fold reduction observed in PCV13-type IPD from 2000 through 2014. This 

included a 3-fold reduction in PCV13-type IPD after PCV13 introduction for children from 2010-

2014. PCV13-type disease incidence among adults 65 years and older declined through indirect 

effects from 45/100,000 before 2000 to 5/100,000 in 20141. Reductions in all-cause pneumonia 

in adults ≥65 years old were demonstrated after pediatric PCV7 introduction in 20002. Analysis 

of Healthcare Cost and Utilization Project (HCUP) data between 2010-2014 presented to ACIP 

did not observe any reductions in all-cause pneumonia, but demonstrated that there were 

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declines from indirect effects in pneumococcal pneumonia of 35% (-40% to -17%) for adults 65-

74 years of age and 20% (-40% to 8%) for adults ≥75 years of age3 [

1Active Bacterial Core 

Surveillance, unpublished data; 2Tsaban et al. 2017; 3Lessa ACIP October 2018].

An inquiry was posed during the last ACIP meeting regarding what indirect effects from pediatric 

PCV13 use have been observed among older adults by age, race, ethnicity, and underlying 

chronic medical conditions. Indirect effects were observed for all age groups. Disparities by age 

in PCV13-type disease were reduced but not eliminated. Indirect effects reduced PCV13-type 

IPD among adults of black race1, Navajos2, and Alaska Natives3. Disparities in PCV13-type IPD 

for Alaska Natives and Navajos versus the general population have been reduced but not 

eliminated. In terms of indirect effects by underlying medical conditions, there has been a similar 

percent reduction in PCV13-type disease amongst adults ≥65 years old with chronic medical 

conditions, including chronic heart, liver, and lung disease; diabetes, alcohol abuse, and 

cigarette smoking as compared to healthy adults1 [1 Active Bacterial Core Surveillance, 

unpublished data; 2 John Hopkins Center for American Indian Health, unpublished data; 3CDC, 

Arctic Investigations Program, unpublished data].

For PCV13 individual-level effectiveness and PCV13 safety, it was known in 2014 that PCV13 

was efficacious in prevention of IPD and non-bacteremic pneumonia. Results from the 

Community-Acquired Pneumonia Immunization Trial in Adults (CAPiTA) showed a 75% 

reduction in vaccine type IPD and a 45% reduction in vaccine type non-bacteremic pneumonia. 

Additionally, PCV13 safety had been demonstrated in clinical trials. In 2014, the GRADE 

evaluation demonstrated a strong quality evidence supporting PCV13 use in series with 

PPSV23 for all adults ≥65 years. Post-licensure data were incorporated into GRADE this year 

and similar conclusions were observed about PCV’s benefits and harms. PCV13 is effective 

against PCV13-type IPD with a VE of 47% to 75%, PCV13-type non-bacteremic pneumonia VE 

of 38% to 71%, and all-cause pneumonia VE of 6% to 11%. There are limited data for PCV13-

type disease mortality. However, no VE has been demonstrated for this outcome. For harms, no 

new safety signals or unexpected patterns have been observed in terms of SAEs associated 

with PCV13.

PCV13 uptake among adults ≥65 years is now 47%, with 30% of adults ≥65 years having 

received both PCV13 and PPSV23. PCV13 coverage among this age group was 36% in 2016 

and 47% in 2018 [Bardenheier. CDC/Immunizations Services Division—Centers for Medicaid 

and Medicare, unpublished data].

In terms of the combined direct and indirect population-level impact on disease since 2014, 

there have been no changes in IPD incidence among adults ≥65 years based on data from 

2013-2017. No continued direct or indirect effects have been observed at the population level 

since 2014. Additionally, non-PCV13 serotypes now make up the majority of the disease 

burden. No population-level impact on mortality has been associated with PCV13-type IPD 

since 2014, nor have there been any changes in the case fatality ratio (CFR)1. Trends in noninvasive pneumococcal pneumonia (NIPP) incidence2 were evaluated from 2013-2016, and 

trends evaluated in NIPP were compared to invasive pneumococcal pneumonia from ABCs1. 

The trends in the two are similar. Incidence was higher for adults ≥65 years as compared to the 

younger age groups, but the trends in the two groups were similar. A decline was observed in 

non-invasive pneumonia between 2013 and 2014 during a period of only indirect effects, but no 

further population-level impact has been seen on non-invasive or invasive pneumonia since 

2014 [1Active Bacterial Core Surveillance, unpublished data; 2Gierke. ACIP October 2018. 

Surveillance for Non-Invasive Pneumococcal Pneumonia (SNiPP), unpublished data].

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A population-level impact on PCV13-type pneumonia was observed in the Pfizer Louisville 

Cohort Study. Reductions of 35.1% in PCV13-type pneumonia and 13.8% in all-cause 

pneumonia were demonstrated between the 2014-2015 year and the 2015-2016 year. PCV13-

type pneumonia was measured to be 4% of all-cause pneumonia versus the 10% that it was 

estimated to be in 2014 [Swerdlow. ACIP June 2018. Pfizer, Louisville Cohort Study, 

unpublished data].

Regarding additional benefits expected from continued PCV13 use among adults ≥65 years 

given the remaining disease burden, PCV13-type IPD disease has remained stable since 2014 

with an incidence of 5/100,000 representing 20% of all IPD. Serotype 3 is not only the most 

common PCV13 serotype, but also is the most common overall for IPD1. For PCV13-type 

pneumonia, incidence ranges from 17/100,0002 to 76/100,0003. Again, PCV13-type 

pneumococcal pneumonia is 4% of all-cause pneumonia and serotype 3 is the most common 

[

1Active Bacterial Core Surveillance (ABCs), unpublished data; 2Gierke. ACIP October 2018. 

Surveillance for Non-Invasive Pneumococcal Pneumonia (SNiPP), unpublished data; 

3Swerdlow. ACIP June 2018. Pfizer, unpublished data].

Two economic models estimated the public health impact and cost-effectiveness of PCV13 in 

series with PPSV23 as compared to PPSV23 alone, the CDC model included two different 

assumptions about the effectiveness of PCV13 against serotype 3 disease. The estimated 

cases averted for PCV13-type IPD were 76 to 175 cases, and 4000 to almost 11,000 for 

PCV12-type pneumonia in a single cohort of 65 year olds. Applying the cost to QALY, the 

estimated cost-effectiveness ratio is between $200,000 and $560,000 per QALY. The annual 

NNV for adults ≥65 years would be 26,000 vaccinated to prevent 1 case of IPD; 3000 to 14,000 

vaccinated to prevent one case of in-patient pneumonia; and 2600 vaccinated to prevent 1 case 

of outpatient pneumonia per year.

There were a few additional important considerations from the EtR framework. First, there are 

limited data regarding the values and preferences of older adults regarding PCV13 use. In 3 

patient-focused studies, participants perceived pneumonia as severe and sometimes fatal1-3. 

However, there was low perceived personal susceptibility to pneumonia1-2. The WG’s 

perspective was that the potential protection against pneumonia likely outweighs the effects of 

PCV13 for older adults [1 Doshi et al. 2016; 2 Brown et al. 2017 (PPSV23 only); 3 Kaljee et al. 

2017].

There also are limited data on assessing acceptability among stakeholders. Based on the 

studies reviewed, some found that current recommendations are confusing for providers1 and 

reimbursement for vaccine is still a programmatic issue for some3. However, in other studies, 

providers recommended continuing with the current recommendation2. Keeping the current 

recommendations also was noted to be a preference programmatically if higher valency 

conjugate vaccines were going to be available soon3. In addition to these study results, the WG 

also noted that frequent changes in recommendations may negatively impact the perceived 

importance of future adult vaccine recommendations. On one side of the argument, continued 

PCV13 use provides individual-level protection for the remaining PCV13 disease burden. But on 

the other side of the argument, continued PCV13 use provides minimal public health benefit due 

to the low remaining disease burden [1 Hurley et al. 2018; 2 Pfizer sponsored provider survey, 

unpublished, 2018; 3 Association of Immunization Managers (AIM) survey, unpublished, 2018].

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When considering feasibility, a number of issues were raised. The current recommendations are 

complex, but have been integrated into many health care and public health systems. Frequent 

changes to recommendations could present implementation challenges. Universal age-based 

recommendations are easier to implement effectively than risk-based recommendations. 

Effective communication strategies will be needed if a policy change occurs. 

In summary, this table compares the key issues favoring continued PCV13 use versus no longer 

using PCV13:

Element Favoring Continued PCV13 Use Favoring No Longer using PCV13

Burden of 

Disease

• PCV13-type disease reduced, but not 

eliminated through indirect effects from 

pediatric PCV use

• Indirect effects from pediatric PCV 

use have reduced the burden of 

PCV13-type disease to historic lows

Benefits • PCV13 effective in preventing PCV13-

type pneumococcal disease

• Impact from PCV13 use in older 

adults observed to date is minimal; 

no impact on IPD and inconsistent 

findings across studies for impact on 

pneumonia

• Benefits from continued PCV13 use 

are expected to be minimal

Acceptability • Frequent changes in recommendations 

may negatively impact the perceived 

importance of future adult vaccine 

recommendations

• Credibility comes from evidencebased recommendations

Resources 

Used

• A recommendation change would incur 

a cost to update electronic medical 

records, decision support tools, etc.

• Economic analyses results do not 

favor continued PCV13 use 

Feasibility • Universal prevention strategies are 

easier to implement effectively than 

risk-based ones 

• Frequent changes in recommendations 

present implementation challenges

• Simplifies the recommendations—

current recommendations have been 

confusing and difficult to implement

In conclusion, the WG agrees that by far, PCV13’s greatest impact for adults has been through 

indirect effects from pediatric use. Since 2014, consistent population-level impact has not been 

observed from PCV13 use amongst older adults. Continuing PCV13 would not be cost-effective 

by usual standards. On the other hand, frequent changes and recommendations may negatively 

impact the perceived importance of adult pneumococcal vaccine programs and present 

implementation challenges. Some WG members weighted more heavily the former strong 

scientific rationale in favor of changing the recommendation, while others weighted more heavily 

the latter acceptability and feasibility issues in favor of maintaining the current recommendation.

Dr. Matanock posted the proposed Policy Options for review and discussion: 

A. Recommend PCV13: “ACIP recommends PCV13 for all adults 65 years or older who have 

not previously received PCV13. PCV13 should be given first, followed by a dose of 

PPSV23.” 

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B. Shared clinical decision making: “ACIP recommends PCV13 based on shared clinical 

decision making for adults 65 years or older who do not have an immunocompromising 

condition and who have not previously received PCV13. All adults 65 years or older should 

receive a dose of PPSV23.”

C. No longer recommend PCV13: “ACIP no longer recommends PCV13 for adults 65 years or 

older who do not have an immunocompromising condition. All adults 65 years or older 

should receive a dose of PPSV23.”

Discussion Points

Dr. Szilagyi said it seemed to him that in this context of immunocompetent persons ≥65 years of 

age, shared decision-making would not depend on an observable behavior or something that 

could be discerned from an interview. This is very different from the previous discussion about 

shared decision-making for HPV vaccine. It was not clear what guidance would be offered to 

clinicians for shared decision-making in this context other than patient values. As a primary care 

physician (PCP), although he does not take care of adults, simplifying something is less 

disruptive and less of a challenge than adding something. That is, this seems like less of a 

challenge than other decisions ACIP has made.

Drs. Frey and Walter also questioned how shared decision-making would be accomplished with 

this vaccine in this context.

Dr. Lee said she thought there was a recognition that the population-level benefit is minimal in 

the context of the indirect effects from the pediatric vaccination program, and that the pediatric 

vaccination program has been the most impactful on adult burden of disease. That said, there 

also is a recognition that there is some individual benefit to patients who may be exposed to 

PCV13-type pneumonia. The challenge is that the burden of disease due to PCV13 specific 

serotypes is low compared to all-cause pneumonia. That particular construct came up because 

of the tension the WG members were having between population-level decision-making versus 

individual-level decision-making. There also is the challenge of recognizing that there is a 

distinction between a risk-based recommendation versus shared clinical decision-making. 

Because they were unpacking this construct during this session, she invited everyone to weigh 

in and comment on it. She could imagine that there are certain populations, such as the 

American Indian/Alaska Native (AI/AN) population, for whom that latitude in decision-making 

may be appropriate to think about populations in which there are higher endemic risk. In that 

situation, it would make sense for a clinician to target that particular population.

Dr. Ezeanolue stressed that there always would be the challenge of population-based benefit 

versus individual-based benefit for vaccines. There always will be some population, however 

small, who will benefit. He did not think that when ACIP said “do not recommend” they were 

passing judgment on whether one person or a small percentage of people may be affected. He 

thought ACIP was tasked to look at the bigger picture and larger perspective and whether 

chasing a smaller population would draw away from the target population. When vaccine is 

available, he thinks everyone should have an opportunity to have it, including the one person 

that it might affect. But the world is a global place. When they expand to smaller populations, 

they draw vaccines away from those who cannot get this vaccination because it is not available 

to them. There is a shift that happens globally when ACIP makes these recommendations for a 

smaller group of people that will pull from what is needed for a very large group of people who 

need the vaccine. In the end, they are not doing the general public good. He asked again 

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whether there is an anticipated shortage of this vaccine, which should help them in making the 

decision.

Dr. Walter thought that the individual-level falls upon the strength of the provider 

recommendation more than shared decision-making in this case. This is not a risk-assessment 

with a patient. It is a provider assessment for their practice in this case.

Dr. Talbot pointed out that it is important to note that there will be newer, better, and more 

comprehensive conjugate vaccines in the near future. Therefore, it may become more 

complicated to remove and then try to add back. In terms of adding back, adults ≥65 years of 

age who are not immunocompromised per se have some immunosenescence, and the 

conjugate vaccines provide B-cell and T-cell responses. Removing the conjugate and allowing 

just the polysaccharide will blunt the future conjugate responses. Therefore, she worried about 

removing PCV13 from an immunologic standpoint for a period of time and leaving a population 

naive.

Dr. Stephens noted that they had previously discussed a prime boost strategy and how that may 

benefit a future platform. He requested an update on the future expanded multi-valent 

conjugate. He agreed with Dr. Talbot about what constitutes immunocompromised. A 65 year 

old with diabetes or chronic obstructive pulmonary disease (COPD) would be considered 

immunocompetent in this group as opposed to a 30-year old individual who is 

immunocompromised, which should be considered in this discussion. One of the challenges has 

been getting any vaccine into the adult population. Vaccination among the eligible group with 

polysaccharide alone was 45% or so, and now the combination vaccine is at almost 60%. Some 

progress has been made with at least getting a vaccine into the adult population with the current 

platform.

Dr. Atmar also expressed interest in knowing when the new conjugate vaccine would become 

available. It seemed to him that this was the kind of discussion about a vaccine that did not 

appear to have public health impact in this population based on the information presented. 

However, the Louisville data clearly show effectiveness of the vaccine in this population. In 

terms of shared decision-making, it is basically about the clinician talking to their patients to let 

them know that the vaccine is effective though not routinely recommended for this age group. 

Some clinicians may promote it more than others in the context of a general pneumonia 

discussion. The default is shared decision-making once a vaccine is licensed, but shared 

decision-making would be a step back from the current recommendation. He did not think 

vaccine availability would be an issue. Because of the effectiveness data, he could not see no 

longer recommending the vaccine in accordance with Policy Option C. While he was moving 

toward the second option, he could be strongly swayed by the implementation issue if a new 

significantly higher multi-valent vaccine would soon become available.

Dr. Hunter said he did not see how things would change by having a higher valent vaccine. 

They still would work better if given to children in terms of protecting adults than giving them 

directly to adults. As a clinician for the past 19 years and now as a public health practitioner for 

the past 10 years, he was very concerned that he had gone from making decisions based on 

individual patient characteristics and how his clinic personally operates to looking at a wide 

variation of clinical practice styles and quality in practice styles across the community and 

country when he gives presentations. He has come to recognize that what really influences the 

decisions clinicians and patients make are the policies that are set up, especially with regard to 

insurance decisions that are made and that those can have population-level effects. As 

somebody who was in the minority on 2 of 3 preferential votes that went in favor of the 

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recombinant zoster vaccine, he has watched with concern as the unexpected lack of supply of 

that vaccine has resulted in missing the second dose of vaccine. For both PCV and HPV, he 

was concerned that emphasizing vaccines for adults over vaccinating children will divert 

resources to the less beneficial, more expensive interventions. If there is not clear guidance or 

suggestions to clinicians about how to do individual clinical decision-making and shared 

guidance for patients, vaccine manufacturers are going to have a vested interested in using 

their significant resources to educate clinicians and patients in a way that might not align with 

public health goals. Unfortunately, there are also significant resources that give information 

directed toward parents of children that is emotionally convincing to them to choose not to 

vaccinate children, which also will detract from the most benefit that can come from these 

vaccines. He thought they needed to be realistic about what they were deciding and not just 

focus on the individual-level, patient-by-patient decisions.

Dr. Bernstein pointed out that the indirect effects of the PCV13 pediatric program on adults 65 

and older is highly impressive. He wondered whether there were any data about decreasing 

rates of PCV13 immunization in children versus current uptake in terms of how that might 

impact adults ≥65 years of age. 

Dr. Moore said that striking to her was the estimated 26,300 NNV of those ≥65 years of age to 

prevent one case of IPD. That number is so incredibly high that shared clinical decision-making 

reflects an uneasiness about dismantling the PCV13 program as it currently exists. Perhaps a 

clearer and more decisive risk-based recommendation might be more appropriate in terms of its 

ability to prevent disease in that group. She shared the thought that it is easier to remove the 

vaccine for a time and introduce a new higher valent at a later date in the near future than it is to 

maintain complex recommendations that have been quite difficult to implement. She also 

expressed concern that if they maintain a PCV13 recommendation until a higher valent vaccine 

is available, consideration would have to be given to whether those ≥65 years of age who 

received PCV13 would also be recommended to receive the higher valent vaccine.

Dr. Messonnier requested that Dr. Lee show the information regarding the two new near future 

pneumococcal conjugate vaccines that are in Phase 3 trials, PCV15 and PCV20. She pointed 

out that all of the companies could tell them when they plan to submit to FDA, but how long 

things may take after that is not knowable.

Dr. Lee shared information showing that both vaccines are conjugated to CRM197 and both 

manufacturers are working toward licensure in adults first. PCV15 includes PCV13 plus 22F and 

33F serotypes and is currently in adult Phase 3 trials. The manufacturer is projecting adult 

Phase 3 completion in approximately the 3rd quarter of 2020 based on clinicaltrials.gov. PCV20 

includes PCV13 plus 8, 10A, 11A, 12F, 15B, 22F, and 33F serotypes. This vaccine is currently 

in adult Phase 3 trials. According to clinicaltrials.gov, the manufacturer is projecting adult Phase 

3 completion by approximately the end of 2019 or early 2020. Dr. Lee emphasized that this 

information was based on the clinicaltrials.gov website, which does not indicate real-time 

updates.

Dr. Luis Jodar (Chief Medical Officer, Pfizer) indicated that Pfizer has stated publicly that they 

are now in Phase 3 clinical trials for the 20-valent and that they are going to file with the FDA by 

the end of 2020. He emphasized that the FDA has given Breakthrough Therapy Designation 

(BTD) to PCV20 for adults. There should not be too much skepticism about the filing or approval 

dates, because these vaccines are based on immunogenicity and non-inferiority. After Phase 2 

they already knew the kind of responses that the common and additional serotypes will have. 

Regarding the comment about PCV20 having the same effect as PCV13 in terms of herd effect, 

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PCV20 will be licensed in adults first and will take a few years before the pediatric indication is 

licensed. It will take 5 to 6 years before herd protection will kick off. The Phase 3 clinical trial 

with a 3+1 in pediatrics takes much longer than a single dose vaccine that will just need to be 

non-inferior to PCV13 and then to PPSV23. 

Dr. Richard Haupt (Merck) confirmed that the timelines are accurate. As Dr. Jodar noted, these 

are immunogenicity studies, so they are not event-driven and are predictable in terms of the 

timeline. The adult indication will come before the pediatric indication, so discussions about how 

to apply a 15-valent vaccine in an adult will come before ACIP before there is a licensed 

pediatric age group vaccine.

In terms of shared clinical decision-making, Dr. Schmader (AGS) pointed out that the health of 

older adults is quite heterogeneous. There are individuals for whom shared decision-making is 

more challenging. For the record, the AGS supports the continued use of PCV13 in older adults 

for all of the reasons listed in favor of PCV13 use.

Dr. Rittle (ANA) indicated that he had communication with the National Black Nurses 

Association (NBNA) and the National Association of Hispanic Nurses (NAHN) in the past couple 

of weeks. Both organizations feel that the current recommendation should be continued. The 

President of the NBNA, Eric Williams, mentioned that there is limited awareness in these 

communities about adult vaccination. There are missed opportunities among healthcare 

providers, payment complexities, financial risks to stock and store vaccines, and limited funding 

for uninsured patients. Norma Cuellar, President of the NAHN, feels that the 2014 National 

Health Interview Survey (NHIS) data coverage information showed that the Hispanic population 

has lower pneumococcal vaccination rates than the non-Hispanic white population, increasing 

the burden of disease among Hispanics. The Hispanic population is often under-represented in 

both statistics and studies completed about the effectiveness of vaccines, and access to 

vaccines in the Hispanic population is often burdened due to social determinants of health 

(SDOH), provider trust, higher insurance rates, and adequate access to care among other 

factors.

Dr. Foster (APhA) commended CDC and the WG for the amount of work put into this. It was 

quite a burden in 2014 when the recommendation was made, and they considered many 

angles. Clinicians like to follow guidelines, particularly in the setting with pharmacy. Pharmacists 

play many roles, and they specifically think about the community pharmacists in terms of 

vaccines. By having a guideline, they know what to do and how to implement it. Pharmacists are 

very busy, so decision-making or confusing issues will result in them not vaccinating. APhA has 

spent a lot of time and resources educating them so that they do understand the current 

guidelines. The problem with too many changes in the guidelines, particularly if a change is 

made again in one more year, is that this will add another difficulty. He was asked to assess the 

opinion of pharmacists. He had the opportunity at the APhA to informally poll a group of about 

300 pharmacists. He went through EtR framework that the WG discussed and presented the 

data to them. Overwhelmingly, these pharmacists felt that because new vaccines are coming, it 

would be much easier and preferred to keep the same guidelines and then revise them when 

the new vaccines are available so that it is not as confusing. The main issue from the 

pharmacist standpoint is the programmatic costs to implement guidelines changes versus the

scientific changes. 

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Dr. Grogg (AOA) indicated that the AOA favors keeping the present guidelines. He gives an 

annual update to their national meeting about ACIP, and he has spent a great deal of time over 

the last 3 years teaching them about the two pneumococcal vaccines. He quipped that if 

changes are made now, they will probably throw things at him when he discusses it.

Dr. Zahn (NACCHO) indicated that NACCHO designated the NACCHO Immunization WG to 

review these data and provide comments to ACIP. Based on their review of the data, the 

NACCHO Immunization WG recommends that at this point, ACIP should no longer recommend 

PCV13 for persons ≥65 years of age who are immunocompetent. The rationale was similar to 

the reasons enumerated, particularly lack of evidence of population-based disease prevented. 

One of the NACCHO Immunization WG’s recommendations was that with any change in the 

recommendation, there should be aggressive communication to providers and local health 

departments to ensure that everyone is providing accurate information and education to 

providers and their patients.

Dr. Whitley-Williams (NMA) indicated that NMA is in support of keeping the current guidelines. 

In spite of the impact from PCV13, she inquired as to whether the data regarding populationlevel impact on IPD and IPD-associated mortality were broken down by ethnicity. She shared 

some of the same ideas as the APhA in that sometimes people of color do get both influenza 

and pneumococcal vaccination at their pharmacies. She suspected that the percent of the 

population would be lower than the numbers who receive these vaccines at a provider’s office. 

She is concerned about risk-based decisions being determined at alternative sites outside of the 

medical home. The assessment of risk, particularly for people in that age group with diabetes 

and other chronic medical conditions, is a concern. Consideration must be given to the fact that 

a change to no longer recommending PCV13 for persons ≥65 years of age may inadvertently 

affect persons of color.

Dr. Rockwell (AAFP) said that AAFP had a divided opinion, so they did not come to consensus. 

However, she gave her word that she would say something on behalf of the COPD Foundation. 

She was approached by the Chief Science Officer to say something about community-acquired 

pneumonia (CAP). She also personally agreed with this in that they are not really looking at the 

effects of this vaccination on the patients who are presenting to the outpatient world and maybe 

never getting to the hospital, or who may be getting treated and getting better because they did 

not get a severe pneumonia.

Dr. Fryhofer (AMA) reported that the AMA as an organization honors the ACIP process in 

making these evaluations. Speaking as an individual practicing physician, she recalled the 

emergency meeting during which this recommendation was made and the CAPiTA study was 

reviewed. When that recommendation was made, it was with the caveat that the information be 

re-evaluated in 2018, which was now done. As a practicing physician, every time a vaccine is 

available that is licensed by the FDA, she has the opportunity for a shared decision-making 

discussion with her patients. However, practicing physicians and the public depend upon ACIP 

to do exactly what the WG did—review all of the studies to determine effectiveness and to tell

the practicing physicians who do not have time to do all of this whether a vaccine really works. 

She would like to know the estimated cost of continuing a vaccine for which there is no evidence 

for another two years. She agreed that it is easier to stop than to add something, but she wants 

her patients to be protected from pneumococcal disease and looks forward to the PCV20 

vaccine being available. Between now and then, they must distribute their resources wisely. 

There is a healthcare crisis in terms of the amount of money being spent on healthcare, and 

thought must be given to how to best use resources. She expressed appreciation for all of the 

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time that was put into reviewing the studies and her trust that they would make the right 

decisions for patients and the country.

Dr. Duchin (IDSA) thanked the CDC team as someone who previously had the privilege of 

service on ACIP and acknowledged that it is critically important for CDC and ACIP to be datadriven and evidence-based in their guidance and recommendations. The IDSA also produces 

recommendations and re-assesses them over time as new data become available and as the 

epidemiology of disease changes, and adjustments are made to their guidance as appropriate. 

He read the official response from IDSA which was asked to weigh in on whether PCV13 should 

be administered routinely to all immunocompetent adults ≥65 years of age in the context of 

indirect effects from pediatric PCV use experienced to date, after careful consideration of the 

evidence and robust discussions made possible by the presentations and sharing of information 

heard during this session with IDSA, a majority of IDSA’s Public Health Committee and Board of 

Directors concluded that, “Given the beneficial indirect effects of pediatric PCV13 vaccination on 

adult pneumococcal disease in the US resulting in a markedly decreased burden of PCV13-

preventable disease, administration of PCV13 routinely to all immunocompetent adults ≥65 

years of age should not be recommended. The key evidence IDSA considered in support of this 

conclusion included that there has been no change in population-level IPD and IPD-related

mortality or pneumococcal pneumonia incidence after the 2014 recommendation beyond that 

attributable to the indirect effects from the PCV13 childhood program; the majority of 

pneumococcal disease burden is comprised of non-PCV-type disease currently, which limits the 

benefit from PCV direct effects; that Serotype 3 is the most common cause of remaining PCVtype disease for which the benefit of vaccine is uncertain; that the NNV to prevent one case is 

approximately 26,000 adults and approximately 2600 to prevent one case of outpatient 

pneumonia per year; and the very high cost of continuing the current recommendation. The 

minority of IDSA representatives who did not support the majority decision raised many of the 

concerns already discussed, particularly that potentially increased vaccination rates would result 

in more noticeable reductions in IPD and IPD-related mortality. However, they recognized the 

low burden of PCV13-type disease that is preventable currently. They were concerned about 

the potential for confusion related to discontinuation of a recommendation, the administrative 

burdens, and the subsequent impact on recommendations for a new vaccine. However, in 

closing, the IDSA’s conclusion is a reflection of the tremendous success of the pediatric PCV13 

vaccination program and its corresponding population health benefits in reducing pneumococcal 

disease burden among adults. IDSA respectfully requests that if ACIP agrees and votes to no 

longer recommend PCV13 be administered routinely, we urge a robust and proactive 

communication strategy for healthcare providers and the public that clearly describes the 

rationale and evidence base for this decision. Thank you for giving IDSA the opportunity to 

provide an official opinion on this important topic.”

Dr. Weiser (IHS) indicated that since the last ACIP meeting, he had a chance to review some 

IHS data and was invited to sit in on some of the discussions with the ACIP Pneumococcal WG. 

IHS has PCV13 coverage of AI/AN ≥65 years of age that has been reported to the IHS 

immunization reporting system. Nationally, about 48% have received the vaccine. This ranges 

by area from less than 20% to 67%. There is either a lack of data or differential uptake. They 

also got to witness some updates to the work that Johns Hopkins has been doing, but there still 

seems to be a lack of data specific to AI/AN to suggest a benefit of PCV13 vaccination to 

immunocompetent adults ≥65 years of age. Limited data on AI/AN subgroups do not 

demonstrate any increase in protection from PCV13 vaccine-type pneumonia or IPD beyond the 

indirect effects achieved with the use of PCV13 in infants. However, those studies are limited to 

Alaska Native, Navajo, and White Mountain Apache Tribes and may not be generalizable to all 

AI/AN. Any changes to the ACIP recommendation for the use of PCV13 in adults ≥65 years of 

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age would have a minimal impact on PCV13 vaccine availability for those high-risk AI/AN adults 

served by IHS who should still receive PCV13. IHS conducted a quick survey of its 

Immunization Coordinators and learned that overall, PCV13 vaccination of adults ≥65 years of 

age has been effectively implemented according to ACIP recommendations per their opinions. 

By a large majority of 92%, the Immunization Coordinators responded that changes to this 

recommendation might have a negative impact on AI/AN adults ≥65 years of age. That reflected 

some of the discussion they heard from others about the implementation issues. IHS did not feel 

that they had enough information to go out on a limb as an agency to say “yes” or “no” for which 

recommendation should be followed.

Dr. Szilagyi pointed out that with regard to the economic analyses and the NNV or the cost per 

QALY, when these models are being done, they do not assume 100% vaccine rates and are 

independent of risk. They are not really modeling shared decision-making. If in shared decisionmaking they can identify high risk patients, the NNV would decrease and the cost per QALY 

would be much lower. If they cannot identify high risk patients, the models would still apply. He 

was worried that in the context of this vaccine, it would be difficult to identify high risk patients in 

shared decision-making, so that the NNV or the cost per QALY would remain what was in the 

model. He was not sure whether that was clear at all.

Dr. Matanock indicated that these models assumed the current vaccination rate. They did 

assess some differential in that they had separate subgroups for those who were healthy, 

though she recognized that “healthy” was not always great term for describing an 85+ year old. 

But, they did separate that group [healthy] into those with chronic medical conditions (heart, 

lung, liver disease; alcohol abuse; et cetera) that are not covered in the immunocompromising 

recommendation. This is the group that should receive PPSV23 based on the 2012 

recommendation.

Dr. Lee commented that in trying to understand the construct of shared clinician decisionmaking across a series of decisions more broadly, from the pharmacy perspective, it is true that 

it is shared decision-making. On the other hand, if a patient walks into a pharmacy and says that 

they know they want PCV13, it seems reasonable to administer the vaccine if the patient feels 

well-informed and wants to receive it. She did not necessarily have a problem with that, but 

thought it depended upon how the construct of “shared clinical decision-making” is defined. 

Does it require a conversation between two people? There are multiple ways people can be 

informed. People are not informed only through their HCP. From the influenza perspective, 

there was a nice summary of recommendations that spoke to the fact that while ACIP 

recommends universal influenza vaccine for anyone 6 months of age and older, there is a 

framework for thinking about how to prioritize people who might be at higher risk (in no 

particular order) in resource-constrained settings. In any given season, they are essentially 

doing this for all patients based on when influenza vaccine becomes available, who the patient 

is seeing, et cetera. Therefore, the dynamic decision-making is essentially happening. As Dr. 

Lee was looking at the influenza construct, it made her realize that they treat vaccines in 

isolation. However, they need something like the adolescent vaccine platform Dr. Middleman 

mentioned years ago for the adult pneumonia prevention platform. There is a lot of 

interrelatedness. Even though they treat vaccines separately and are trying to make decisions 

separately, they are trying to protect the same populations.

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Ms. McNally said that she was struggling with the public trust in this organization in that they 

were making decisions based on current data. She did not want the current data to erode the 

trust that they have in other vaccines and the importance of them at the time. She appreciated 

the concern about the use of resource and the fact that they do not anticipate that future

introduction of vaccines will change the outcome in terms of the population-level impact.

Dr. Stephens said that in his view, the issue was about prevention of pneumonia. Data were 

provided in the handouts indicating that the estimated cases averted of pneumonia for the 

cohort of adults ≥65 years of age was 4,000 to 10,000 for PCV-type pneumonia.

Dr. Matanock clarified that what was in the package was that 4,000 to 10,000 cases of PCV13-

type pneumonia are the cases averted for a cohort of adults ≥65 years of age, while what was in 

the presentation was the annual NNV. It is important to note that the annual NNV is different 

from the NNV for a cohort. For a cohort, there is the benefit of that vaccine for whatever the 

assumptions are in the model. Those come from the same health economics model. The 4000 

to 10,000 cases averted was over the lifetime of the cohort. That is the difference between using 

PCV13 + PPSV23 in series versus PPSV23 alone.

Dr. Foster (APhA) commented that it is important to keep in mind that state practice determines 

what pharmacists are permitted to do. Every state has its own board that makes these 

decisions. Pharmacists operate under Standing Orders that dictate what they can or cannot do, 

and typically Standing Orders instruct them to follow ACIP guidelines. If Standing Orders do not 

state to follow ACIP guidelines, someone who walks in requesting a vaccine may not receive it.

Dr. Moore commented that as she had more time to reflect, it seemed that part of their dilemma 

was that there were two main choices: 1) prioritize operational concerns by not changing 

anything, which prioritizes the operational evidence; and 2) remove the recommendation, which 

prioritizes the epidemiologic evidence. She thought their struggle was that both were legitimate 

points of view with very legitimate questions to be answered. She thought the shared clinical 

decision-making was an attempt to split the difference, but she had some concern that it could 

inadvertently make things more complicated.

Dr. Maldonado (AAP) pointed out that they were looking at two different things, vaccine 

efficacy/effectiveness versus the population benefits. If it is an FDA-approved vaccine, it is 

efficacious. The question regarded vaccine efficacy and the direct effects of the vaccine 

subtracted from the indirect effects. For example, is there a population for which the direct 

effects are actually stable or increasing? There may be additional information that they were not 

seeing with regard to direct effects, which may be masked by the indirect effects. A control 

group is needed that is comprised of people who were vaccinated and did not get sick in order 

to show the direct effects, but she did not think they had seen that. She worried about that in 

terms of identifying populations, especially with regard to populations who may not be 

vaccinated appropriately and whether there are pockets where direct effects are showing some 

impact on the disease. She also looked at a recent meta-analysis of the effect of herd immunity 

on adult IPD, which suggested that it takes about 2 to 3 years for PCV13 to reach a 50% 

reduction in disease, but it would take about 8 to 9 years to get to a 90% rate. She wondered 

whether perhaps it was too early to see the what is actually occurring and if that number would 

decrease even further. Even that does not clarify the issue of the direct versus indirect effects. 

Those are two separate issues.

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Dr. Matanock replied that effectiveness studies have shown effectiveness of this vaccine. No 

impact has been observed at the population-level, meaning that no continued indirect effects or 

direct effects have been seen at the population-level and they are now close to 10 years postPCV13 introduction and more since conjugate vaccines have been used for children.

Dr. Mahon (NCIRD) mentioned that in the space of shared clinical decision-making, it would be 

possible to identify some groups that would be at higher risk that would provide assistance to 

clinicians if ACIP decided to go in that direction. The group that meets the definition of 

immunocompromising conditions is not part of this policy decision. That group will be 

recommended to receive both vaccines regardless. There are additional data about groups who 

are at higher risk that could be identified to assist practitioners in clinical decision-making.

Dr. Messonnier clarified that she was trying to draw a parallel between the HPV discussion and 

the clinical considerations language that the HPV WG showed, with the idea being that that 

language would be provided in a different fashion to clinicians in order to provide some help to 

them in how to think about this. The Pneumococcal WG did not display that kind of language, 

but there are clinical considerations that could be provided if Policy Option B was approved.

Regarding the point raised about disparities, Dr. Matanock indicated that they do have 

information about this and shared it with ACIP previously. Disparities were presented to ACIP by 

race and ethnicity, which showed that disparities amongst older adults of black race have been 

eliminated through indirect effects. The disparities for AI/AN have been reduced through indirect 

effects, but not completely eliminated. She agreed that this important point should continue to 

be assessed, because there are other factors such as access involved.

Dr. Luis Jodar (Chief Medical Officer, Pfizer) agreed that the discussion had been about the 

epidemiology viewpoint versus programmatic and implementation issues. As a representative of 

the manufacturer, he wanted to discuss the epidemiology viewpoint. Dr. Matanock showed 

PCV13 vaccine effectiveness of 6% to 11% in all-cause pneumonia, which represents 

approximately 30,000 hospitalizations in the CDC data. That was not included in any of the costeffectiveness calculations. He thought it was important to recognize that this is a gigantic public 

health impact rather than no public health impact. This is not isolated in that it has been 

corroborated in Germany and the Netherlands. There also were a lot of technical discussions 

about NNV. In all of the models, the NNV was for one year. This conjugate vaccine has shown 

at a minimum 5 years of protection. The NNV might need to be divided by 5 to reflect the real 

picture of NNV. When talking about public health impact, this should be taken into consideration 

by ACIP.

Dr. Lee said that while this was a difficult decision and there were three differing viewpoints on 

table, because of the way the PICO question was asked and the way the evidence was 

reviewed, it made sense to her to make a motion to approve Policy Option A to recommend 

PCV13 for all adults 65 years or older who have not previously received PCV13. PCV13 should 

be given first, followed by a dose of PPSV23.

Dr. Hunter made a motion to approve Policy Option C to no longer recommend PCV13 for 

adults 65 years or older who do not have an immunocompromising condition. All adults 65 years 

or older should receive a dose of PPSV23.

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Dr. Romero clarified that when this happens, ACIP refers to Roberts Rules of Order such that 

the motion that would move forward for seconding would come from the Chair of the 

Pneumococcal WG, which would be Dr. Lee. However, she already made the motion to approve 

Policy Option A. Therefore, Dr. Romero called for anyone who wished to second Dr. Lee’s 

motion. Dr. Atmar seconded the motion made by Dr. Lee.

Dr. Cohn reminded everyone that they would stay the motion, which would be voted on 

subsequent to public comment, and that further votes could be considered if the first motion did 

not pass. For continuity, the vote and related discussion are included here.

Motion/Vote #1: Continue to Recommend PCV13 for All 

Adults ≥65 Years of Age Not Previously Vaccinated with PCV13 

Dr. Lee made a motion to approve the proposed recommendation text for Policy Option A to 

continue the current recommendation reading, “ACIP recommends PCV13 for all adults 65 

years or older who have not previously received PCV13. PCV13 should be given first, followed 

by a dose of PPSV23.” Dr. Atmar seconded the motion. No COIs were declared. The motion

failed with 6 affirmative votes, 8 negative votes, and 0 abstentions. The disposition of the vote 

was as follows:

 6 Favored: Bernstein, Ezeanolue, Moore, Stephens, Talbot, Walter

 8 Opposed: Atmar, Ault, Frey, Hunter, Lee, McNally, Romero, Szilagyi

 0 Abstained: N/A

Discussion Following The Vote

Dr. Romero invited the members to share the rationale for their votes.

Dr. Lee said that she voted “no” because looking at the overall evidence in terms of burden of 

disease, preventability, cost-effectiveness, and population-level benefit, she felt that it was 

challenging to continue this recommendation. While she recognized and very much appreciated 

the implementation challenges and agreed with all of the comments made by all of the members 

and liaisons, she felt the need to focus on the evidence base in this instance.

Mc. McNally echoed Dr. Lee’s comments. This was a very difficult decision, but for those 

reasons she chose to vote “no.”

Dr. Ault said that he had very mixed feelings about this vote as well. It has been known for more 

than a century that pneumococcus is a killer of men and women, especially in this age group. 

However, he felt that he needed to follow the evidence and vote “no.” He also echoed what Dr. 

Lee said.

Dr. Szilagyi indicated that he voted “no” for the same reasons, including the epidemiologic 

data/evidence, the remarkable success of the pediatric program in terms of indirect benefits, 

and the overall public health implications.

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Dr. Talbot said that she voted “yes” because she likes the prime boost, especially in the

population with immunesenescence. The current polysaccharide vaccine does not prevent 

pneumonia in older adults. This is very important because pneumonia can take away a person’s 

independence.

Dr. Atmar said he voted “no” for many of the reasons already stated. He was not ultimately 

persuaded that implementation difficulties that would accrue, if and when there is a higher 

valent vaccine, would occur soon enough to outweigh the evidence of lack of effect for the 

general public at large.

Dr. Bernstein indicated that he voted “yes” because it was incredibly impressive how ACIP has 

handled this issue over the years since the recommendation was first made in 2014 and the 

intent to reassess the recommendation after a number of years. He was almost swayed by the 

evidence and certainly the indirect impact of the pediatric PCV13 program. However, there is 

still a significant amount of disease in those 65 years of age and older. He also believes there 

will be potential implementation issues as well.

Dr. Ezeanolue said that he voted “yes” because there is still a significant amount of disease in

those older than 65 years of age. The vaccine has been shown to be very effective in this age 

group. The reason they are not seeing a difference is because there is herd immunity from the 

pediatric population. The herd immunity could decrease and this would put older adults at risk. 

They should have the opportunity to get a vaccine that is known to work very well, and there is a 

public health need for it. There is not an impact because of herd immunity, but they are counting 

on that when it may not be there for a long time.

Dr. Stephens said he voted “yes” because this was a retreat from the platform they have had for 

a number of years that he thought was the right platform moving forward (e.g., conjugate 

followed by polysaccharide). He was swayed by the evidence that this vaccine does prevent 

pneumonia in adult patients, though perhaps not significant IPD. As mentioned earlier, the term 

“immunocompromised” in this particular population is a difficult one and one that ACIP should 

address in the future. Though the current platform may not be ideal and broader conjugates are 

needed since most IPD and pneumonia is caused by non-PCV serotypes due to the remarkable 

impact of the pediatric vaccine. Conversely, this is a message that ACIP is retreating from the 

conjugate platform that has been effective in the older population.

Dr. Moore said that she voted “yes” to retain the current recommendation not because she felt 

like it was obviously the choice. It was a very difficult choice with evidence on both sides, 

epidemiologic and evidence of operational disruption. They did not really talk about the cost 

associated with transforming every heath system in the country to adjust to a change in this 

recommendation. She would rather spend that money on vaccine where there might be some 

epidemiologic evidence missing that the studies simply have not yet captured. Knowing how 

disruptive a change in recommendation is, she would rather have all of the disruption take place 

at once with the advance of a new more multi-valent conjugate vaccine. Weighing those two 

very narrowly calculated risks and benefits, she erred on the side of not making a change, 

leaving things alone until a later data, and making all of the changes at once.

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Dr. Hunter said he voted “no” for very similar reasons. As with HPV, he thought they were 

diluting the message that vaccinating children is important. He was interpreting the advent of the 

higher valent vaccines as positive, but felt the need to send a message to the manufacturers 

because while it is easier to conduct the studies with adults due to Institutional Review Board 

(IRB) issues, that is not where the public health “bang for the buck is.” It is among children and 

that is what they should be doing.

Dr. Walter said that he voted “yes” due to the potential for direct benefit to prevent pneumonia 

and due to the potential operational issues discussed.

Dr. Frey indicated that she voted “no” because the indirect effects of vaccinating children is 

quite strong. This vaccine is effective and she does have concerns about immunocompromised 

hosts, but they were not voting on them. She does have concerns about older adults with other 

underlying co-morbidities. She leaned more toward the epidemiology than the logistics because 

she does not want to give a vaccine to someone if it is not necessary.

Dr. Romero said that he voted “no” for all of the reasons previously stated.

Motion/Vote #2: No Longer Recommend PCV13 for All 

Adults ≥65 Years of Age Not Previously Vaccinated with PCV13 

Dr. Hunter made a motion to approve the proposed recommendation text for Policy Option C to 

continue the current recommendation reading, “ACIP no longer recommends PCV13 for adults 

65 years or older who do not have an immunocompromising condition. All adults 65 years or 

older should receive a dose of PPSV23.” Dr. Ault seconded the motion. No COIs were declared. 

The motion failed with 1 affirmative vote, 13 negative votes, and 0 abstentions. The disposition 

of the vote was as follows:

 1 Favored: Hunter 

 13 Opposed: Atmar, Ault, Frey, Bernstein, Ezeanolue, Lee, McNally, Moore, Romero, 

Szilagyi, Stephens, Talbot, Walter

 0 Abstained: N/A

Discussion After The Vote

Dr. Romero invited members to share their rationales for their votes.

Dr. Hunter indicated that he voted “yes” for no longer recommending PCV13 for adults 65 years 

or older who do not have an immunocompromising condition because he thinks that clinicians 

need a clear message, and it is going to be very difficult to clinical decision-making that is going 

to be implemented. This would have been easier to explain to clinicians than the clinical 

decision-making.

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Motion/Vote #3: Recommend Shared Clinical Decision-Making for 

PCV13 for Adults ≥65 Years of Age Not Previously Vaccinated with PCV13 

Dr. Lee made a motion to approve the proposed recommendation text for Policy Option B 

implement shared clinical decision-making reading, “ACIP recommends PCV13 based on 

shared clinical decision-making for adults 65 years or older who do not have an 

immunocompromising condition and who have not previously received PCV13. All adults 65 

years or older should receive a dose of PPSV23.” Ms. McNally seconded the motion. No COIs 

were declared. The motion carried with 13 affirmative votes, 1 negative votes, and 0 

abstentions. The disposition of the vote was as follows:

 13 Favored: Atmar, Ault, Frey, Bernstein, Ezeanolue, Lee, McNally, Moore, Romero, 

Szilagyi, Stephens, Talbot, Walter

 1 Opposed: Hunter 

 0 Abstained: N/A

Discussion After The Vote

Dr. Romero invited members to share their rationales for their votes.

Dr. Messonnier acknowledged that this was complicated and difficult, and CDC will think about 

how to simplify it. They need to make sure that in the ACIP statement this is not communicated 

as an 11 to 1 vote, because that misses the sequences of votes that ACIP went through.

Dr. Bernstein said that he considered it to be shared clinical decision-making with all vaccines. 

He voted “yes” initially, so this was a compromise. He agreed that it would be important to 

explain the sequence of the votes in the MMWR guidance.

Dr. Lee thanked the WG and ACIP members. Even with this decision, she was feeling a heavy 

weight upon her. She does think that there is strong individual benefit to patients, so she feels 

like having access to this vaccine is very important. She also strongly believes that a better 

pneumonia prevention program is needed, and that they need to be thoughtful about how to 

approach this from a broader perspective.

Dr. Szilagyi agreed with both of the statements Dr. Lee made and noted that he really struggled 

with this decision. As discussed before, he thought a lot more research and thought were 

needed in the area of shared decision-making and identifying high risk groups. The group of 

individuals 65 years and older who are not immunocompromised is not a homogeneous group. 

He was swayed by the AI/AN subgroups and there may be additional subgroups. Like many 

things, there is a lack of optimal evidence. That is part of clinical care.

Dr. Ezeanolue said that he voted “yes” because he was concerned about reliance on herd 

immunity and he wanted to ensure that people who live in places where herd immunity is low or 

decreased have an opportunity for a shared decision to get the vaccine.

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Introduction

Kelly Moore, MD, MPH

Chair, Combination Vaccines WG

Vanderbilt University School of Medicine

Dr. Moore reported that the Combination WG has been focusing on a pediatric hexavalent 

vaccine over the last couple of months. This vaccine is a joint venture with Merck and Sanofi 

Pasteur that combines the following antigens:

 Diphtheria, tetanus, pertussis (DTaP5)

 Polio (IPV)

 Haemophilus influenzae type b (Hib; PRP-OMP)

 Hepatitis B (Hep B)

The official abbreviation is DTaP-IPV-Hib-HepB. The dashes in between indicate that each 

component is liquid. This vaccine is intended to be given in a 3-dose series at 2, 4, and 6 

months. The Biologics License Application (BLA) was approved and licensed by the FDA on 

December 21, 2018. It is important to note that the manufacturer has stated that this vaccine will 

not be available commercially prior to 2021 in order to assure adequate supply to meet 

demands.

In terms of the policy topics under consideration initially by the WG, the first was to consider 

whether the new pediatric hexavalent vaccine should be preferentially recommended for the 

AI/AN population. The second was to consider whether the new pediatric hexavalent vaccine 

should be included as an option in the Vaccines for Children (VFC) Program for the infant series 

at 2, 4, and 6 months of age. The preferential recommendation would have required an ACIP 

policy vote. There was discussion during the February 2019 meeting regarding some of the 

reasons the WG had not advised moving forward on that. The recommendation to add this 

vaccine to the VFC Program requires only a VFC vote.

As a reminder, February 2019 ACIP presentations included: 1) Immunogenicity and Safety of 

Pediatric Hexavalent Vaccine by Andrew Lee, Merck; 2) Hib Epidemiology and Vaccines in 

AI/AN Population by Laura Hammitt, Center for American Indian Health, Johns Hopkins; and 3) 

Summary and Review of Work Group Considerations by Sara Oliver, CDC/NCIRD. 

Since then, the WG has had a number of calls during which they reviewed safety and 

immunogenicity data, Hib epidemiology and Hib vaccines among the AI/AN population, and use 

of combination vaccines in an infant series and discussed policy options. Later in 2019, they will 

publish the MMWR Policy Note related to this new vaccine.

The agenda for this meeting included a presentation summarizing WG discussions, relevant 

components to the EtR recommendations framework for this vaccine, and VFC votes.

Combination Vaccines

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Summary and Relevant EtR Framework

Sara Oliver MD, MSPH

CDC WG Lead, Haemophilus Influenzae Subject Matter Expert

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Oliver first briefly reviewed the topics under consideration and then presented the relevant 

aspects of the EtR Framework and the WG interpretation. As a reminder, the two policy topics 

under deliberation include consideration of whether the new pediatric hexavalent vaccine should 

be preferentially recommended for the AI/AN population and whether the new pediatric 

hexavalent vaccine should be included as an option in the VFC Program for the infant series at 

2, 4, and 6 months of age.

In the pre-vaccine era, Hib disease occurred at a younger age among the AI/AN population 

compared to the general US population. Dr. Hammitt’s February 2019 presentation showed a 

peak of Hib meningitis at 4-5 months of age among Native American children, compared to 6-9 

months in the general US population. In addition, PRP-OMP vaccines can achieve protective 

immunity in a majority of infants after the first dose. Dr. Hammitt also highlighted the ability of 

PRP-OMP vaccines to achieve protective immunity in 91% of infants after the first dose, much 

higher than what was seen with other Hib vaccines. It is because of these factors, to provide 

necessary protection early in infancy, that PRP-OMP vaccines are preferentially recommended 

for the AI/AN population. That preferential recommendation was based on immunogenicity data 

after the first dose. The available data after the second and third dose for the new hexavalent 

vaccine show a robust response. However, there are no data post-dose 1, which would provide 

important information for the window of vulnerability seen in this population.

Because of this, the WG and ACIP members felt that immunogenicity data post-dose 1 are 

needed before ACIP could consider a preferential recommendation for the AI/AN population. 

Given that, Dr. Oliver indicated that she would be presenting only the relevant EtR framework 

on the second topic (e.g., to consider whether the new pediatric hexavalent vaccine should be 

included as an option in the VFC Program). She explained that at this time, there was no 

proposed ACIP vote that would change current ACIP policy. The only vote would pertain to 

adding an additional vaccine option to the VFC Program. Because of this, the full EtR

Framework was not undertaken. However, to present evidence in a standard and transparent 

format, there are aspects of the EtR Framework that are relevant for the new combination 

vaccine: Benefits and Harms, Values, Acceptability, and Feasibility. Dr. Oliver presented

available evidence related to these aspects.

In terms of potential benefits, given that all components of the pediatric hexavalent vaccine are 

currently licensed and recommended, the immunogenicity studies conducted were noninferiority studies comparing each antigen in the new vaccine to currently licensed vaccines.

Overall, non-inferiority criteria were met, with 2 exceptions. First, non-inferiority was not met for 

the geometric mean concentrations (GMCs) for one of the 5 pertussis antigens, filamentous 

hemagglutinin (FHA), at the post-dose 3 time point. However, it was achieved with the percent 

that met a pre-specified vaccine response. Next, 1 of the 13 pneumococcal antigens, 6B, 

missed the pre-specified non-inferiority endpoint post-dose 3. However, it would have met the 

non-inferiority endpoints used in the PCV13 studies.

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As mentioned in February, antigen or serotype-specific correlates of protection are unknown, so 

it is unclear whether these differences are clinically relevant. However, there are 5 pertussis 

antigens included in the vaccine, and only one antigen at one time point did not meet the pre-set 

non-inferiority criteria. In addition, the non-inferiority criteria were met for all other PCV13 

antigens. Serotype 6B rarely causes invasive pneumococcal disease among US children in the 

post PCV13 era. Regarding the benefits of combination vaccines in general, combination 

vaccines merge equivalent component vaccines into a single product to prevent more than one 

disease. An increased number of vaccine doses due is associated with deferring doses, leading 

to missed opportunities and decreased coverage1. However, the receipt of at least 1 

combination vaccine has been found to be associated with improved coverage rates, both 

among individual vaccines as well as for completion of the full infant vaccine series2 [1Meyerhoff 

et al. Preventative Medicine 2005; 540-544; 2Marshall et al. Pediatr Infect Dis J 2007; 496-500].

In terms of potential harms of the new hexavalent vaccine, the vaccine has an overall safety 

profile consistent with the licensed component vaccines. There was a higher rate of fever, 

particularly when compared to pentavalent regimens. However, there was no increase in feverrelated medical events, such as hospital visits or febrile seizures. With regard to potential harms 

of combination vaccines in general, as stated in ACIP’s General Best Practice Guidelines for 

Immunization1, potential disadvantages of combination vaccines include AEs that might occur 

more frequently after administration of a combination vaccine compared with administration of 

separate antigens; confusion and uncertainty about selection of vaccine combinations and 

schedules for subsequent doses, especially when vaccinations are given by multiple providers 

who might be using different products; reduced pathogen coverage if the combination product 

covers fewer types of one particular vaccine-preventable disease-causing agent; extra doses of 

certain antigens could be given in the combination product; and there is potential for a shorter 

shelf-life than in individual component vaccines. Not all of these potential disadvantages would 

apply to the specific hexavalent vaccine [1General Best Practice Guidelines for Immunization. 

Best Practice Guidance of the ACIP. https://www.cdc.gov/vaccines/hcp/acip-recs/generalrecs/index.html].

Regarding values and preferences, there are no specific data about the new hexavalent vaccine 

and values of the target population. However, ACIP and the American Academy of Pediatrics

(AAP) have statements regarding the value of combination vaccines. The ACIP General Best 

Practice Guidelines for Immunization states that, “Use of combination vaccines can reduce the 

number of injections patients receive and alleviate concern associated with the number of 

injections. The use of a combination vaccine generally is preferred over separate injections of 

the equivalent component vaccines. Considerations should include provider assessment, 

patient preference, and the potential for adverse events1.” In addition, the 2018 Red Book states 

that, “Combination vaccines represent one solution to the issue of increased numbers of 

injections during single clinic visits and generally are preferred over separate injections of 

equivalent component vaccines2 [1General Best Practice Guidelines for Immunization. Best 

Practice Guidance of the ACIP. https://www.cdc.gov/vaccines/hcp/acip-recs/generalrecs/index.html; 2American Academy of Pediatrics. Red Book 2018 Report of the Committee on 

Infectious Diseases. 31st Edition]. 

Moving to acceptability, there have been no specific studies regarding the new hexavalent 

vaccine and acceptability among stakeholders. However, there have been evaluations for the 

acceptability of combination vaccines overall. A prior evaluation of combination vaccines in 2003 

among Medicaid patients in Georgia showed that 85% of children received at least 1 

combination vaccine in the first year of life [Marshall et al. Pediatr Infect Dis J 2007; 496-500].

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For a more recent assessment, the frequency of combination vaccines and single vaccines for 

the infant series in multiple birth cohorts from 2014 to 2018 was evaluated using data from the 

Immunization Information Systems (IIS). The evaluation assessed 2 different antigens: DTaP 

and Hib. This evaluation was conducted at 6 IIS sentinel sites. The IIS systems have providersubmitted, population-based data that are timely and cover all pediatric ages. However, given 

that it is only 6 sites, the information may not always be generalizable. There are 2 pentavalent 

combination vaccines that contain DTaP. Over 90% of DTaP doses over this timeframe were 

given in a combination vaccine. When assessed with Hib antigen, which is included in only 1 

pentavalent vaccine, 40% to 60% of Hib doses were given in a combination vaccine [Michelle 

Lin, CDC’s Immunization Services Division].

In terms of feasibility, the additional combination vaccine will not alter the established 

vaccination schedule. As the vaccine is licensed only for the primary series at 2, 4, and 6 

months of age and not a booster dose, there will need to be consideration for having additional 

product or products available for booster doses. As mentioned earlier, the new vaccine will not 

be commercially available prior to 2021. 

In summary, the WG reviewed relevant evidence to consider whether the new pediatric 

hexavalent vaccine should be included as an option in the VFC Program for the infant series at 

2, 4, and 6 months of age. The balance of benefits and harms would support making the 

vaccine an available option. The target population appears to value combination vaccines in 

general, and this seems acceptable to key stakeholders. Therefore, the overall interpretation of

the evidence was that the WG unanimously supported the inclusion of this vaccine in the VFC 

Program as one of the available options. 

Discussion Points

Dr. Atmar requested clarification regarding whether there still would be a preferential 

recommendation for AI/AN populations if the new vaccine was added to the VFC schedule.

Dr. Oliver indicated that the preferential recommendation would remain for the single antigen 

Hib PRP-OMP vaccine unless post-dose 1 data become available. Essentially, there would be 

no change in the vaccine schedule for the AI/AN population at this point.

Dr. Moore added that the WG is very hopeful that there will be post-dose 1 data available for 

their review close to the time the vaccine is anticipated to enter the marketplace.

Ms. Hayes (ACNM) inquired as to how this combination vaccine would impact the birth dose of 

HepB vaccine.

Dr. Oliver replied that the birth dose is still recommended. The combination vaccine is not 

licensed for the birth dose and would be given at 2, 4, and 6 months.

Given that this vaccine will not become available until 2021, Dr. Hunter inquired as to whether 

ACIP voting now was going to help AIM and other groups be prepared when it is available.

Ms. Finley (AIM) replied that this was correct and that it also would allow time to consider what 

educational information they would provide.

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VFC Resolution Updates: New DTaP-IPV-Hib-Hep B Vaccine

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch presented the VFC resolution updates for the new DTaP-IPV-Hib-HepB vaccine. 

He reminded everyone that in December 2018, a new combination vaccine was licensed: DTaPIPV-Hib-Hep B. In order to include this vaccine in the VFC program, updated VFC resolutions

had to be prepared for each of the affected vaccine types (DTaP, IPV, Hib, and Hep B) for 

review and consideration by ACIP. The impetus of the resolution updates was to incorporate the 

new combination vaccine into the list of currently available vaccines in the VFC program. 

Additionally, they took this opportunity to update portions of the resolution language to more 

closely reflect the current ACIP recommendations when appropriate. Yellow highlighting was 

used to indicate changes to the resolution in comparison to the prior approved version.

The first VFC resolution update was for diphtheria, tetanus, and pertussis vaccines. The 

purpose of this resolution was to update the “Recommended Schedule and Intervals” section 

using tables and language adapted from the most recent ACIP recommendations, and to reflect 

the currently available vaccines that can be used to prevent diphtheria, tetanus, and pertussis.

No changes were proposed to the eligible groups, which include children and adolescents aged 

6 weeks through 18 years.

Two new tables were added to the Recommended Schedule and Intervals section that were 

adapted from the current ACIP recommendations, with the new combination vaccine 

incorporated into the first of these tables. 

Vaccines containing tetanus toxoid, diphtheria toxoid, and acellular pertussis antigens and age 

for approved use by vaccine type for persons aged < 7 years: 

Vaccine Type Vaccine Brand (1) Age for approved use in the 

routine schedule (2)

2 

mos

4 

mos

6 

mos

15-18 

mos

4-6 yrs 

(3)

DTaP DTaP (4) Daptacel X X X X X

DTaP (4) Infanrix X X X X X

Combination 

vaccines with 

DTaP

DTaP-HepB-IPV 

(4, 5)

Pediarix X X X

DTaP-IPV/Hib (4, 

6)

Pentacel X X X X

DTaP-IPV-HibHepB (4, 7)Vaxelis X X X

DTaP-IPV (8) Kinrix X

DTaP-IPV (8) Quadracel X

DT DT (4, 9) None X X X X X

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The notes remain the same as in the existing resolution except for those shown in yellow. The 

second table note was added to show minimal intervals, the seventh table note provides specific 

information about VAXELISTM, and the ninth table note updates language about the use of TD 

vaccine from the existing VFC resolution using language from the current ACIP 

recommendations:

(1) The use of brand names is not meant to preclude the use of other comparable licensed 

vaccines.

(2) Minimal intervals: Dose 1 to 2: 4 weeks. Dose 2 to 3: 4 weeks. Dose 3 to 4: 6 months. Dose 

4 to 5: 6 months. For more information on age for use in catch-up immunization schedules 

please see: https://www.cdc.gov/vaccines/schedules/hcp/imz/catchup.html 

(3) The fifth dose is not necessary if the fourth dose was given after the fourth birthday. 

(4) FDA approved for use in infants as young as 6 weeks.

(5) FDA-approved for use through age 6 years (prior to 7th birthday). The combined DTaPHepB-IPV vaccine may be used when any component of the combination is indicated, and if 

the other components are not contraindicated. Approved for the primary series only (Doses 

1-3). For adequate immune response, the last dose of hepatitis B vaccine should be given at 

≥24 weeks of age and therefore this combination vaccine should not be administered as a 

complete primary series on an accelerated schedule at 4-week intervals for prevention of 

pertussis. 

(6) FDA-approved for use through age 4 years (prior to 5th birthday). The combined DTaPIPV/Hib vaccine may be used when any component of the combination is indicated, and if 

the other components are not contraindicated. Approved for the primary series and first 

booster dose (Doses 1-4). The combined DTaP-IPV/Hib vaccine is not indicated for children 

5 years of age and older. 

(7) FDA-approved for use through age 4 years (prior to 5th birthday). The combined DTaP-IPVHib-HepB vaccine may be used when any component of the combination is indicated, and if 

other components are not contraindicated. Approved for the primary series only (Doses 1-

3). For adequate immune response, the last dose of hepatitis B vaccine should be given ≥24 

weeks of age and therefore this combination vaccine should not be administered as a 

complete primary series on an accelerated schedule at 4-week intervals for prevention of 

pertussis. 

(8) The combined DTaP-IPV vaccines may be used when any component of the combination is 

indicated, and if the other components are not contraindicated. Only approved for the 

booster dose at age 4 through 6 years. Earlier doses should use another vaccine. 

(9) Use diphtheria and tetanus toxoids vaccine if encephalopathy not attributable to another 

identifiable cause occurs within 7 days of administration of previous dose of pertussiscontaining vaccine.

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The second new table shows the vaccines approve in persons aged 7 to 18 years and also is 

adopted from the current ACIP recommendations:

Vaccines containing tetanus toxoid, diphtheria toxoid, and acellular pertussis antigens and age 

for approved use by vaccine type for persons aged 7-18 years: 

Vaccine Type Brand Age for Approved Use

Tdap (1, 2, 3, 4) Adacel 10 - 18 years

Boostrix 10 - 18 years

Td (4, 5) Tenivac 7 - 18 years

TDVAX 7 - 18 years

The first table note has been updated to reflect the guidance about the use of Tdap as included 

in the current ACIP recommendations. The second table note was included in the existing VFC 

resolution, but it was updated with information about additional Tdap vaccination in children who 

received a dose of Tdap as part of the catch-up series. This information is taken from the 

current ACIP recommendation. The third table note has been updated and table notes 4 and 5 

were not part of the existing resolution, but were included to reflect the current ACIP 

recommendations. The update in item 3 provides information about the timing of Tdap 

vaccination during pregnancy, while new notes 4 and 5 provide guidance for tetanus 

prophylaxis, wound management, and language related to contraindications for Td vaccine: 

1) Tdap is indicated for a single booster dose at age 11 or 12 years. Adolescents who did not 

receive Tdap at age 11 or 12 should receive a single dose of Tdap. Tdap can be 

administered regardless of interval since the last tetanus or diphtheria containing vaccine.

2) Tdap should be given to children aged 7-18 years of age who have received tetanus and 

diphtheria containing vaccine (DT or Td) instead of DTaP for some or all doses of the 

childhood series; have received fewer than 5 doses of DTaP or 4 doses if the fourth dose 

was administered at age 4 years or older; or have never been vaccinated against tetanus, 

diphtheria, or pertussis (no doses of pediatric DTaP/DT or Td). The preferred schedule is a 

single Tdap dose, followed by a dose of Td four weeks after the first dose and a second 

dose of Td 6-12 months later. If not administered as the first dose, Tdap can be substituted 

for any of the other Td doses in the series. For persons aged 7–10 years who receive a 

dose of Tdap as part of the catch-up series, an adolescent Tdap vaccine dose should be 

administered at age 11–12 years. More information about the catch-up is available at: 

https://www.cdc.gov/vaccines/schedules/hcp/imz/catchup.html#note-tdap 

3) Adolescents who are pregnant should receive Tdap, irrespective of past history of Tdap 

receipt. Tdap should be administered between 27 and 36 weeks’ gestation, preferably 

during the earlier part of this time period, although it may be administered at any time during 

pregnancy. If an adolescent did not receive Tdap during her current pregnancy and did not 

receive a prior dose of Tdap ever, then Tdap should be administered immediately 

postpartum. If an adolescent did not receive Tdap during her current pregnancy but did 

receive a prior dose of Tdap, then she should not receive a dose of Tdap postpartum.

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4) A tetanus toxoid-containing vaccine may be indicated for tetanus prophylaxis for wound 

management. For more details, see: 

https://www.cdc.gov/mmwr/volumes/67/rr/rr6702a1.htm. 

5) Td should be used if encephalopathy not attributable to another identifiable cause occurs 

within 7 days of administration of previous dose of pertussis-containing vaccine.

 

No changes were made to “Recommended Dosages, Contraindications, and Precautions” or the 

Statement Regarding Update Based on Published Documents”: 

Recommended Dosages, Contraindications, and Precautions

Recommended Dosages 

 Refer to product package inserts. 

Contraindications and Precautions 

 Contraindications and precautions can be found at: 

https://www.cdc.gov/mmwr/volumes/67/rr/rr6702a1.htm. 

Statement Regarding Update Based on Published Documents

[If an ACIP recommendation regarding vaccination against diphtheria, tetanus, and pertussis is 

published within 6 months following this resolution, the relevant language above (except in the 

eligible groups sections) will be replaced with the language in the recommendation and 

incorporated by reference to the publication URL.]

Discussion Points

Regarding the schedule, Dr. Moore thought the final dose for HepB was ≥24 weeks of age 

versus >24 weeks as shown on the schedule.

Dr. Oliver confirmed that this should be ≥24 weeks of age and would be revised.

Regarding pregnant teenagers and Tdap on the table notes for the second table, Ms. Hayes 

(ACNM) thought the sentence at the end of note 3 reading “If not administered during 

pregnancy, Tdap should be administered immediately postpartum” should be removed as 

postpartum vaccines are no longer being recommended. She emphasized the importance of 

this being consistent for adults and pregnant teens. 

Dr. Havers, the Pertussis WG lead indicated that the current recommendation states that it can 

be administered postpartum and it is recommended if the woman has not previously received a 

Tdap vaccine. The wording could be amended to clarify that.

Regarding table note 2 for the first table, Dr. Bernstein pointed out that the minimal intervals 

should be Dose 1 to 2: 4 weeks, Dose 2 to 3: 4 weeks, Dose 3 to 4: 6 months, and Dose 4 to 5: 

6 months rather than Does 5 to 6: 6 months.

Dr. Frey requested clarification on whether this should be preferentially recommended.

Dr. Cohn clarified that they were not making a policy change. When there is a new type of 

vaccine product, ACIP must vote to include it in the VFC program. This is an option to be used 

to follow the schedule. They would not be voting on any recommendation related to the AI/AN 

population.

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Motion/Vote #1: Changes to the VFC Resolution for DTaP 

Dr. Moore made a motion to accept the revised VFC Resolution for DTaP as corrected with the 

comments made during the discussion period with respect to intervals and other errors. Dr. 

Walter seconded the motion. No COIs were declared. The motion carried with 14 affirmative 

votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Update: Hib Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch presented the VFC resolution updates for Haemophilus influenzae type b (Hib) 

vaccines. The purpose of this resolution was to update the “Recommended Vaccination 

Schedule and Intervals” section to reflect the list of currently available Hib-containing vaccines 

that can be used to prevent Hib disease and to add a clarifying footnote about the timing of the 

booster dose that is included in the most recent recommendations. Yellow highlighting indicates 

changes to the resolution in comparison to the prior approved version.

No changes were proposed to eligible groups, which include all children 6 weeks to 18 years of 

age, to prevent Hib disease. 

The recommended schedule includes 3 or 4 doses of a Hib-containing vaccine, depending on 

the specific vaccine. The “Recommended Schedule/Dosage Intervals” Table 1 was updated to 

include VAXELISTM, table note 4 was included to clarify the timing of the booster dose for 

PENTACEL®, table notes 5 and 6 were added for VAXELISTM: 

Vaccine Brand (1) Components Primary

Series

Booster Dose

Monovalent vaccines 

PRP-OMP (2,3) PedvaxHIB PRP conjugated to 

OMP

2, 4 months 12 – 15 months 

PRP-T ActHIB PRP conjugated to 

tetanus toxoid

2, 4, 6 

months 

12 – 15 months 

PRP-T Hiberix PRP conjugated to 

tetanus toxoid 

2, 4, 6 

months 12 – 15 months 

Combination vaccines 

DTaP-IPV/Hib Pentacel DTaP + IPV + PRP-T 2, 4, 6 

months 

15 – 18 months 

(4) 

DTaP-IPV-Hib-HepB 

(5) 

Vaxelis DTaP + IPV + PRPOMP + HepB 2, 4, 6 

months

Not licensed (6) 

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(1) Use of brand names in Table 1 is not meant to preclude the use of other licensed Hib 

vaccines with similar active components. 

(2) If a PRP-OMP vaccine is not administered as both doses in the primary series or there is 

uncertainty about which products were previously administered, a third dose of Hib 

conjugate vaccine is needed to complete the primary series.

(3) Preferred for American Indian/Alaska Native children.

(4) The booster dose may be administered as early as age 12 months, provided that at least 6 

months have elapsed since the third dose.

(5) Not preferred for AI/AN children due to lack of immunogenicity data after the first dose. 

(6) DTaP-IPV-Hib-HepB is not licensed for a booster dose; any other Hib conjugate vaccine 

licensed for the booster dose can be used.

No updates were made to Table 2 “Minimum Age and Intervals for Hib Vaccines” or the 

associated notes:

Minimum Age

Minimum Intervals

Primary Series (Up to 12 

months)

Minimum Interval

Booster dose (12 

months and older)

6 weeks 4 weeks 8 weeks

 The ACIP recommends Hib vaccine for all children through 5 years of age. In addition, 

children less than 24 months of age who develop invasive Hib disease should be considered 

unvaccinated and receive Hib vaccine doses according to the age-appropriate schedule for 

unimmunized children. Vaccination or re-vaccination of children <24 months of age who 

develop invasive Hib disease should begin 4 weeks after disease.

 If Hib vaccination is not initiated by 6 months of age, use the following schedule shown in 

Table 3. (next slide)

No updates were made to Table 3 “Catch-Up Vaccination Schedule”: 

Age at First 

Vaccination

Primary Series Booster

7-11 months 2 doses, at least 4 weeks apart Age 12-15 months at least 8 

weeks after the second 

dose*

12-14 months 2 doses, at least 8 weeks apart N/A

15-59 months 1 dose N/A

*A booster dose at 12 - 15 months of age is only necessary if 2 or 3 primary doses (depending on vaccine type used) were 

administered before age 12 months. 

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No updates were made to Table 4 “Guidance for Hib Vaccination in High-Risk Groups” or its 

footnotes: 

High-Risk Group* Hib Vaccine Guidance

Patient <12 months of age Follow routine Hib vaccination recommendations

Patients 12-59 months of age If unimmunized or received 0 or 1 dose before age 12 

months: 2 doses 2 months apart 

 

If received 2 or more doses before age 12 months: 

1 dose 

 

If completed a primary series and received a booster 

dose at age 12 months or older: no additional doses

Patients undergoing 

chemotherapy or radiation 

therapy, age <59 months†

If routine Hib doses given 14 or more days before starting 

therapy: revaccination not required 

If dose given within 14 days of starting therapy or given 

during therapy: repeat doses starting at least 3 months 

following therapy completion

Patients undergoing elective 

splenectomy, 

>15 months-18 years

If unimmunized§: 1 dose prior to procedure ‡

Asplenic patients, 

>59 months–18 years

If unimmunized§: 1 dose 

HIV-infected children,

>59 months -18 years 

If unimmunized§: 1 dose 

Recipients of hematopoietic 

stem cell transplant, 

through18 years

Regardless of Hib vaccination history: 3 doses (at least 1 

month apart) beginning 6-12 months after transplant

Footnotes for Table 4: 

*Patients with functional or anatomic asplenia, HIV infection, immunoglobulin deficiency 

including Immunoglobulin G2 subclass deficiency, or early component complement deficiency, 

recipients of a hematopoietic stem cell transplant (HSCT), and those receiving chemotherapy 

for malignant neoplasms.

† Some experts suggest conducting serologic testing for these patients. 

‡Some experts suggest vaccination at least 14 days before the procedure; some experts 

suggest administering a dose prior to elective splenectomy regardless of prior vaccination 

history.

§ Patients who have received a primary series and booster dose or at least 1 dose of Hib 

vaccine after 14 months of age are considered immunized.

No changes were made to “Recommended Dosages, Contraindications, and Precautions” or the 

Statement Regarding Update Based on Published Documents.”

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Motion/Vote #2: Changes to the VFC Resolution for Hib Vaccines 

Dr. Moore made a motion to accept the revised VFC Resolution for Hib vaccines as presented. 

Dr. Szilagyi seconded the motion. No COIs were declared. The motion carried with 14 

affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Update: Hepatitis B Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch presented the VFC resolution updates for Hepatitis B Vaccines. The purpose of 

this resolution was to update the “Recommended Vaccination Schedule and Intervals” section to 

reflect the currently available hepatitis B-containing vaccines that can be used to prevent 

hepatitis B. Yellow highlighting indicates changes to the resolution in comparison to the prior 

approved version.

No changes were made to eligible groups, which include all children and adolescents from birth 

through 18 years of age. The tables listing the acceptable vaccination schedules for children 

and adolescents from birth through 18 years of age was not changed: 

Single Antigen Vaccine Single-antigen1 and combination 

vaccine2,3,4

Birth 

weight 

Maternal 

HBsAg 

status 

Dose Age Dose Age 

≥2000 g Positive 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs )1

2 1-2 months 2 2 months 

3 6 months 3 4 months 

4 6 months 

Unknown 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs)1

2 1-2 months 2 2 months 

3 6 months 3 4 months 

4 6 months 

Negative 1 Birth (≤24 hrs)1 1 Birth (≤24 hrs)1

2 1-2 months 2 2 months 

3 6 -18 months 3 4 months 

4 6 months 

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<2000 g Positive 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs)1

2 1 month 2 2 months 

3 2-3 months 3 4 months 

4 6 months 4 6 months 

Unknown 1 Birth (≤12 hrs)1 1 Birth (≤12 hrs)1

2 1 month 2 2 months 

3 2-3 months 3 4 months 

4 6 months 4 6 months 

Negative 1 Age 1 month or at 

hospital discharge1

1 Age 1 month or at 

hospital discharge1

2 2 months 2 2 months 

3 6 -18 months 3 4 months 

4 6 months 

For the table notes, additional information was added to the PEDIARIX® [DTaP-IPV-HepB] to 

match the PEDIARIX® footnote in the DTaP VFC resolution, which provides guidance about 

minimum intervals. Table note 3 was added for VAXELISTM [DTaP-IPV-Hib-HepB]: 

1. Only a single antigen hepatitis B vaccine (ENGERIX-B or RECOMBIVAX HB) can be given 

at birth.

2. Pediarix [DTaP-IPV-HepB] is licensed for children 6 weeks through 6 years of age. For 

adequate immune response, the last dose of hepatitis B vaccine should be given >24 weeks 

of age and therefore this combination vaccine should not be administered as a complete 

primary series on an accelerated schedule at 4-week intervals for prevention of pertussis. 

3. Vaxelis [DTaP-IPV-Hib-HepB] is licensed for children 6 weeks through 4 years of age. For 

adequate immune response, the last dose of hepatitis B vaccine should be given >24 weeks 

of age and therefore this combination vaccine should not be administered as a complete 

primary series on an accelerated schedule at 4-week intervals for prevention of pertussis. 

4. Use of brand names is not meant to preclude the use of other comparable US licensed 

vaccines. 

No changes were made to “Table 2: Children and Adolescents” or its table notes: 

Age Schedule1, 6

Children (1 through 10 years) 0, 1, and 6 months2

0, 2, and 4 months2

0, 1, 2, and 12 months2,4

Adolescents (11 through 18 years) 0, 1, and 6 months2

0, 1, and 4 months2

0, 2, and 4 months2

0, 12, and 24 months2

0 and 4-6 months3

0, 1, 2, and 12 months2,4

0, 7 days, 21-30 days, 12 months5

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Table Notes

1. Children and adolescents may be vaccinated according to any of the schedules indicated, 

except as noted. Selection of a schedule should consider the need to optimize compliance with 

vaccination.

2. Pediatric/adolescent formulation.

3. A two-dose schedule of Recombivax-HB Adult Formulation is (10 micrograms) is licensed for 

adolescents aged 11 through 15 years. When scheduled to receive the second dose, 

adolescents aged > 15 years should be switched to a three-dose series, with doses 2 and 3 

consisting of the pediatric formulation administered on an appropriate schedule. 

4. A four-dose schedule of Engerix B is licensed for all age groups. 

5. Twinrix can be administered to persons 18 years of age before travel or any other potential 

exposure on an accelerated schedule at 0, 7, and 21-30 days, followed by a dose at 12 months. 

6. Use of brand names is not meant to preclude the use of other comparable US licensed 

vaccines.

No changes were made to the “Interrupted Schedules and Minimum Dosing Intervals” or 

“Revaccination” sections:

Interrupted schedules and minimum dosing intervals

 When the HepB vaccine schedule is interrupted, the vaccine series does not need to be 

restarted. If the series is interrupted after the first dose, the second dose should be 

administered as soon as possible, and the second and third doses should be separated by 

an interval of at least eight weeks. If only the third dose has been delayed, it should be 

administered as soon as possible. 

 The final dose of vaccine must be administered at least eight weeks after the second dose 

and should follow the first dose by at least 16 weeks; the minimum interval between the first 

and second doses is four weeks. Inadequate doses of hepatitis B vaccine or doses received 

after a shorter-than-recommended dosing interval should be re-administered, using the 

correct dosage or schedule. 

 Vaccine doses administered ≤4 days before the minimum interval or age are considered 

valid. Because of the unique accelerated schedule for Twinrix®, the four-day guideline does 

not apply to the first three doses of this vaccine when administered on a 0 day, 7 day, 21-30 

day, and 12 month schedule. 

 In infants, administration of the final dose is not recommended before age 24 weeks (164 

days). 

Revaccination

Revaccination (i.e., booster dose, challenge dose, or revaccination with a complete series) is 

not generally recommended for persons with a normal immune status who were vaccinated as 

infants, children, or adolescents. Revaccination when anti-HBs is <10 mIU/mL is recommended 

for the following: 

 Infants born to HBsAg-positive mothers

 HBsAg-negative infants with anti-HBs <10 mIU/mL should be re-vaccinated with a single 

dose of HepB vaccine and receive post vaccination serologic testing 1-2 months later. 

Infants whose anti-HBs remains <10 mIU/mL following single dose revaccination should 

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receive two additional doses of HepB vaccine, followed by PVST 1-2 months after the 

final dose. 

• Based on clinical circumstances or family preference, HBsAg-negative infants 

with anti-HBs <10 mIU/mL may instead be revaccinated with a second, complete 

3-dose series, followed by post vaccination serologic testing (PVST) performed 

1-2 months after the final dose of vaccine.

 Hemodialysis patients. For hemodialysis patients, the need for booster doses should be 

assessed by annual anti-HBs testing. A booster dose should be administered when anti-HBs 

levels decline to <10 mIU/mL. 

 Other immunocompromised persons. For other immunocompromised persons (e.g., HIVinfected persons, hematopoietic stem-cell transplant recipients, and persons receiving 

chemotherapy), the need for booster doses has not been determined. When anti-HBs levels 

decline to <10 mIU/mL, annual anti-HBs testing and booster doses should be considered for 

persons with an ongoing risk for exposure. 

 Persons with postvaccination serologic testing results that do not demonstrate protection. 

This includes children and adolescents through age 18 years who are chronic hemodialysis 

patients, HIV-infected, otherwise immunocompromised (e.g., hematopoietic stem-cell 

transplant recipients or persons receiving chemotherapy), or sex partners of HBsAg-positive 

persons. Persons in these groups found to have anti-HBs concentrations of <10 mIU/mL 

after the primary vaccine series should be revaccinated. 

No changes were made to “Recommended Dosages, Contraindications, and Precautions” or the 

Statement Regarding Update Based on Published Documents.”

Motion/Vote #3: Changes to the VFC Resolution for Hepatitis B Vaccines 

Dr. Moore made a motion to accept the revised VFC Resolution for Hepatitis B vaccines as 

presented. Dr. Frey seconded the motion. No COIs were declared. The motion carried with 14 

affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Update: Polio Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch presented the VFC resolution updates for polio vaccines. The purpose of this 

resolution was to update the “Recommended Vaccination Schedule and Intervals” section to 

reflect the currently available inactivated polio vaccine (IPV) and IPV-containing vaccines that 

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can be used to prevent polio. Yellow highlighting indicates changes to the resolution in 

comparison to the prior approved version.

No changes were made to eligible groups, which include all infants and children aged at least 

six weeks of age. 

VAXELISTM was added to the recommended schedule, which identifies single antigen and 

combination vaccines licensed and currently available for routine use to prevent polio and a link 

was added for additional details:

Vaccine Brand(s) Schedule Comments

IPV Ipol 2,4,6-18 mos; 4-6 yrs Approved for use in infants and 

adults

DTaP-HepB-IPV Pediarix 2,4,6 mos Approved for first 3 doses of IPV 

through 6 yrs

DTaP-IPV/Hib Pentacel 2,4,6 and 15-18 mos Approved for 4 doses of IPV 

through 4 yrs

DTaP-IPV-Hib-HepB Vaxelis 2,4,6 mos Approved for first 3 doses of IPV 

through 4 yrs

DTaP-IPV Kinrix, 

Quadracel

4-6 yrs Approved for booster dose at age 

4-6 yrs

Additional details can be found at:

https://www.cdc.gov/mmwr/preview/mmwrhtml/mm5830a3.htm?s_cid=mm5830a3_e* 

No changes were made to “Recommended Dosages, Contraindications, and Precautions” or the 

Statement Regarding Update Based on Published Documents.”

Motion/Vote #4: Changes to the VFC Resolution for Polio Vaccines 

Dr. Moore made a motion to accept the revised VFC Resolution for Polio vaccines as 

presented. Dr. Walter seconded the motion. No COIs were declared. The motion carried with 14 

affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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Thomas Clark, MD, MPH

Deputy Director, Division of Viral Diseases

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Clark provided an update on the current measles outbreaks in the US. For context, the 

implementation of single dose of measles-containing vaccine dramatically reduced the burden 

of morbidity and mortality associated with measles in the US. However, a resurgence of disease 

in the late 1980s resulted in both a second dose recommendation prior to school entry and 

contributed to the formulation of the VFC Program to reduce disparities due to socioeconomic 

status (SES) in vaccination.

Coverage with measles-containing vaccine overall has been sustained at high levels in the US. 

One plus dose coverage among toddlers is 90% to 91% nationwide, but ranges from about 

82.5% to over 98%. Drivers of under-immunization nationally are related to access. Within 

states, pockets of under-immunization exist in communities that are under-immunized by 

choice. Those communities are not reflected in state-level maps [Source: National Immunization 

Survey-Child (NIS-Child), 1995 through 2017 available online through CDC ChildVaxView at 

https://www.cdc.gov/vaccines/imz-managers/coverage/childvaxview/data-reports/index.html].

To date in 2019, there have been 1077 cases of measles confirmed in 28 states. This is the 

greatest number of cases reported in the US since measles was declared eliminated in 2000. In 

fact, this is the highest number since 1992 at the tail-end of the resurgence of measles. There 

are currently five ongoing measles outbreaks associated with New York State, Rockland 

County; New York City; California, Butte County; Pennsylvania, Allegheny County; and 

Washington, King County. In the last three of these, it has been more than 21 days since the 

last case onset. Therefore, CDC is hopeful that these outbreaks will be over soon. However, the 

New York City and New York State outbreaks are ongoing. Those outbreaks began at the end 

of September 2018 and have been sustained through 2019.

Because measles has been eliminated, all cases and all outbreaks are associated with 

importations due to travel overseas. High 2-dose coverage has been critical in eliminating or 

limiting transmission when cases are imported. However, when cases are imported into 

communities with low coverage, measles can spread and expose individuals who are 

unvaccinated. There have been 13 outbreaks reported in the use this year. Of these, 94% of the 

total case count have been associated with outbreaks. Of the 13 outbreaks, 6 were in underimmunized, close-knit communities such as in Rockland County and New York City. Those two 

outbreaks have contributed 77% of the case counts nationwide. Since the end of 2018, there 

have been over 640 cases in New York city and over 340 in Rockland County. Of the cases, 64 

(6%) were internationally imported. Of those cases, 44 (69%) were US residents and 20 (31%) 

were foreign visitors. The 3 most common source countries from which importations have 

occurred are the Philippines (15 imports), Ukraine (10 imports), and Israel (9 imports). The 

global context for these importations is a 3-fold increase in measles globally. Measles are 

endemic in much of the world, and there are large outbreaks in many parts of the world. The 

countries that have imported cases reflect to some degree the burden of disease globally, but 

especially reflect travel patterns and the likelihood of exposing under-immunized communities.

Measles Update

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Since early April 2010, CDC has been operating in an Incident Management Structure operated 

out of NCIRD. Over 100 staff are working on the response. Case counts and outbreak 

information are updated on the website weekly. They are working especially to promote 

vaccination of travelers and prevention of importations, especially through air contact 

investigations. They have provided technical assistance to states reporting measles cases, 

including prevention and control measures, and vaccine implementation and work to support 

case confirmation and genotyping, especially through the vaccine-preventable disease 

collaborations with the state public health laboratories. They are able to provide on-ground 

assistance when requested, and have had over 25 staff deployed to Rockland County, New 

York to assist the state and county with their outbreak. They have been especially working to 

provide evidence-based information and targeted communications resources to promote 

awareness of measles and of the benefits of vaccination, and to establish collaborations with 

key stakeholders in affected communities (e.g., Rabbis/Rabbinical organizations, healthcare 

providers, health centers, and summer camps). At the end of April, they published an MMWR

report the experience with measles with the 704 cases to date that describes the clinical 

presentation, complications, et cetera.

In summary, the US remains in measles elimination status, although there are prolonged 

outbreaks in close-knit communities that CDC is working to bring under control. Vaccination 

coverage remains high, but communities with low vaccination coverage are at risk for outbreaks. 

In the context of increased global measles activity, risk of continuing importations is expected.

Discussion Points

Dr. Schaffner (NFID) asked what could/would put the US’s status of having eliminated measles 

at risk.

Dr. Clark replied that measles elimination was declared after more than a year of no endemic 

transmission. A year of sustained endemic transmission would put the status at risk, so CDC is 

working hard to support getting ahead of these outbreaks before that happens.

Dr. Kimberlin (AAP) noted that when children under a year of age travel internationally, they are 

recommended to receive MMR if they are between 6 through 11 months of age. He wondered 

what the recommendation within the US would be.

Dr. Clark indicated that in general, everyone could be reassured that the risk of measles in most 

of the US is low. CDC is recommending that travelers who intend to go to communities where 

there is sustained transmission and where they are likely to be exposed to populations in which 

measles are being transmitted to follow the recommendations made by the local health 

departments. There is a narrow circumstance, with most people not being at high risk for 

measles in the US or from travel across the US.

Dr. Lee thought it would be interesting for ACIP to hear about how CDC has tailored 

implementation strategies depending upon the contextual factors and what they have found to 

be most effective.

Dr. Stephens inquired about the level of vaccine coverage in communities where there have 

been sustained outbreaks.

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Dr. Clark said that in some cases, it has been a challenge to understand coverage in these 

communities. These are very local phenomena and the immunization registries are not always 

optimal. Even in New York and Rockland County, it has been a challenge to understand the 

denominators. They do not absolutely know prior coverage in these communities. Many doses 

have been delivered in New York City and Rockland County, so they appear to be improving 

coverage.

Dr. Hahn (CSTE) commented that it is challenging for state and local health departments to 

message the need for immunization when outbreaks are going on. She wondered whether there 

might be other language they could use, such as “transmission has been interrupted.” It is 

difficult to say, “It has been eliminated, but it is here and we have more cases.”

Dr. Clark said that they have bridged this by stating that all cases of measles in the US are 

associated with travel, which puts the communities travelers come into at risk.

Dr. Hunter asked whether there are any administrative or logistical implications of losing 

elimination status such as insurance coverage or ability to use 317 vaccines in certain 

situations.

Dr. Clark said that there should not be. Of course, it is important to re-establish elimination 

status, but this should not have practical implementation implications for the vaccination 

program.

Dr. Bernstein asked what relationship CDC has with the countries that have thousands to tens 

of thousands of cases of measles, and how the agency is working with those countries if at all.

Dr. Clark indicated that CDC’s Global Immunization Division works closely on measles globally 

with many countries. CDC is in constant communication with PAHO and WHO regarding the 

US’s status and with respect to situational awareness with these countries. In certain 

circumstances, CDC is trying to promote specific travel-associated prevention measures with 

travel from some specific countries.

Introduction

Kelly Moore, MD, MPH

ACIP Chair, Zoster WG

Vanderbilt University School of Medicine

In terms of the Zoster WG’s activities, Dr. Moore reminded everyone that in October 2017, ACIP 

voted to recommend recombinant zoster vaccine (RZV) for adults ≥50 years of age. In June 

2018, plans were described to monitor the safety, effectiveness, and uptake of RZV. In February

2019, preliminary results were presented of uptake and safety, including a statistical signal for 

Guillain-Barré Syndrome (GBS). She indicated that the purpose of the presentation for this 

session was to present a follow-up on the results for RZV safety monitoring.

Zoster Vaccines

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Update on Post-Licensure Safety Monitoring of RZV (SHINGRIX) 

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office 

Centers for Disease Control and Prevention

Dr. Shimabukuro provided an update on safety monitoring from the Vaccine Adverse Event 

Reporting System (VAERS), Rapid Cycle Analysis (RCA) from the Vaccine Safety Datalink 

(VSD), FDA assessment of GBS following recombinant zoster vaccine (RAV) from Medicare 

data, and next steps. He first clarified a few of the terms that are used in the context of vaccine 

safety monitoring and research, which are shown in the following table:

As a reminder, RZV is an adjuvanted (AS01B) glycoprotein vaccine that was licensed in October 

2017 and is preferentially recommended by ACIP for adults ≥50 years. Initial post-licensure 

safety data was presented during the February 2019 ACIP meeting. Overall, the safety profile of 

RZV was consistent with pre-licensure clinical trial data. A statistical signal was detected for 

GBS in VSD RCA monitoring based on a small number of GBS cases using automated data. 

Signal assessment is in progress, including a FDA analysis of Medicare data. 

Beginning with VAERS monitoring, VAERS is a spontaneous reporting system that is comanaged by CDC and FDA. As a spontaneous reporting system, its main limitation is that 

generally causality cannot be assessed from VAERS data alone. VAERS accepts all reports 

from all reporters without making judgments on causality, irrespective of clinical seriousness. As 

a hypothesis generating system, VAERS identifies potential vaccine safety concerns that can be 

studied in more robust data systems. 

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CDC performed a descriptive analysis of RZV reports from October 2017 through April 2019

and estimated reporting rates based on 11.89 million RZV doses distributed for the US market 

through March 2019. FDA colleagues conducted Empirical Bayesian (EB) data mining to detect 

disproportional reporting for vaccine-AE pairings. A clinical review was performed of reports for 

the 20 pre-specified outcomes shown below:

During the analytic period, there were 18,418 total reports. Of those, 12,431 (67.5%) were in 

females and 17,919 (97.3%) were non-serious. In 94% of reports, RZV was given alone without 

other vaccines. The reporting rates for all reports were 154.3 per 100,000 doses distributed and 

3.9 per 100,000 doses distributed for serious reports. Those are similar to what was reported in 

February 2019 and similar for other vaccines given in this age group. Systemic signs and 

symptoms and injection site reactions were the most commonly reported AEs, and no 

unexpected patterns were detected by physician reviewers of reports of pre-specified outcomes. 

EB data mining identifies AEs that are reported more frequently than expected, adjusting for 

age, sex, and the year in which reports are received. There has been one empirical EB data 

mining finding to date for RZV, which was “product administered to patient of inappropriate age”

when looking at individuals 19 through 44.9 years of age.

In summary, RZV post-licensure safety monitoring findings in VAERS are generally consistent 

with the safety profile observed in pre-licensure clinical trials. Self-limited systemic signs and 

symptoms and injection site reactions were the most commonly reported adverse events. SAEs

were rarely reported (2.7% of reports), which is similar to other vaccines given in the same age 

group. There have been no EB data mining findings for any RZV-AE pairings except for “product 

administered to patient of inappropriate age.” 

Regarding the RCA in the VSD, there are 8 participating integrated healthcare organizations in 

the VSD collaborating with CDC: Kaiser Permanente Washington, Kaiser Permanente 

Northwest, Kaiser Permanente Northern California, Kaiser Permanente Southern California, 

Kaiser Permanent Colorado, HealthPartners, Marshfield Clinic Research Institute, and Harvard 

Pilgrim. The VSD has medical care and demographic data on over 12.1 million persons per year 

(~3.7% of U.S. population), including data on immunizations, encounters with the healthcare 

systems, hospital discharge codes, procedure codes, and demographic information all linked by 

unique study IDs. CDC also has access to electronic files and paper charts. RCA in the VSD is 

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a powerful and sophisticated tool for near real-time vaccine-safety monitoring using sequential 

monitoring techniques. It employs an automated analysis that uses ICD-coded diagnoses from 

administrative data. It is a surveillance activity (signal detection and signal refinement), which is 

not the same as an epidemiologic study (signal evaluation, causality assessment). It is designed 

to detect statistical signals, which are values above specified statistical thresholds. When a 

statistical signal occurs, CDC conducts a series of evaluations using traditional epidemiologic 

methods. Chart-confirmation of diagnoses to confirm or exclude cases as true incident cases is 

a key part of statistical signal assessment. Importantly, not all statistical signals represent a true 

increase in risk for an AE.

For RZV RCA, a historical comparator design is used to compare current RZV recipients to 

zoster vaccine live (ZVL) recipients from 2013 to 2017 for the risk window of 1 to 42 days. 

Monthly near real-time sequential monitoring is done of pre-specified outcomes. During this 

session, Dr. Shimabukuro presented data from the 7th of 18 planned analyses. The test statistic

is an adjusted likelihood ratio test (H0: RR=1 versus HA: RR>1). These are the 10 high priority 

pre-specified RZV RCA outcomes:

High Priority Pre-Specified Outcomes Risk Interval

in Days

 Acute myocardial infarction 1-42

 Anaphylaxis 0-1

 Bell’s palsy 1-42

 Convulsion 1-42

 Giant cell arteritis 1-42

 Guillain-Barré syndrome 1-42

 Optic ischemic neuropathy 1-42

 Polymyalgia rheumatica 1-42

 Stroke 1-42

 Supraventricular tachycardia 1-42

Other outcomes for descriptive analysis include: gout, keratitis, non-specific adverse effects, 

stroke subtypes, pneumonia, keratitis, uveitis and retinitis, zoster ocular disease, systemic 

reactions, local reactions, and urgent care or emergency department visits. 

A secondary analysis also is being done using two concurrent comparators comparing RZV 

recipients to those who: 1) had an ICD-10 coded well-visit during RZV uptake period; and 2) 

received another vaccine that was not influenza (e.g., PPSV23, PCV13, Td, Tdap, et cetera) 

during the RZV uptake period. For the 7th analysis, just over 211,000 doses had been 

administered in the VSD through December 2018 with follow-up for outcomes through April 

2019. This is a summary table of the RCA results for the high priority outcomes:

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No statistical signals were detected for any of the high priority outcomes with the exception of 

Bell’s Palsy and GBS. GBS signaled previously, which was presented to ACIP during the 

February meeting.

Bell’s Palsy signaled at the 5th analysis. At that time, there was a relative risk (RR) of 1.51 with 

36 observed events versus 24 expected events (p=0.03). By the 7th analysis, it had attenuated 

somewhat to an RR of 1.31 with 40 observed events versus 31 expected events. Importantly, 

the RR are not consistently elevated for the concurrent comparator groups. The RR are actually 

0.98 in the well-visit comparator group and 0.74 in the other non-influenza vaccine recipients. 

Chart review adjudication was performed on the 36 RZV cases from the 5th analysis, which 

ruled out 21 cases (11 prevalent/non-incident; 5 miscoded; 2 diagnosis overturned; 3 outside 1-

42 day risk window) and classified 15 cases as definite with onset within the 1 to 42 day

window. That is a chart confirmation rate of about 40%. Bell’s Palsy reports that came into 

VAERS also were reviewed. There were no EB data mining findings or proportional reporting 

ratio (PRR) findings for Bell’s Palsy. After review and adjudication of the Bell’s Palsy reports, a 

reporting rate of 1.2 cases per million RZV doses distributed was estimated.

GBS signaled at the 2nd analysis at which time there were 3 observed events versus 0.6 

expected for a RR of 5.25. Currently at the 7th analysis, there are 5 observed events compared 

to 1.6 expected events for a RR of 3.18. Of the 5 events, 2 were ruled out due to prior diagnosis 

of GBS so they were not true incident cases and 1 was ruled out due to GBS symptom onset 

prior to vaccination. Of the 2 confirmed cases, 1 was a Brighton Criteria level 2 GBS case with 

onset in the risk window who also received simultaneous PCV13 and 1 was a Brighton Criteria 

level 3 GBS case with onset in the risk window and probable respiratory infection prior to GBS 

symptom onset. 

As part of the statistical signal assessment for GBS, all of the GBS cases in the historical ZVL 

comparators were reviewed. Upon chart review of these 5 cases in the historical comparator, 2 

cases were ruled out, 1 due to prior diagnoses of GBS and 1 who was given an alternative 

diagnosis of chronic inflammatory demyelinating polyneuropathy (CIDP). Medical records were 

not available for 1 case, so it was not possible to confirm/rule out. There were 2 Brighton 

Criteria level 2 confirmed GBS cases with onset in the risk window. So that is 2 confirmed cases 

from RZV at the 7th analysis and 2 confirmed cases following ZVL in the historical ZVL cohort.

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To date, the estimated VSD chart confirmed GBS rate in the current RZV cohort is higher than 

in the historical ZVL cohort, and higher than published estimates in the literature1,2. However, 

the uncertainty around the VSD estimated GBS rate following RZV is large, IR=8.2 (95% CI 1.0, 

29.7), and overlapping with the background rates reported in the literature. They decided to 

perform a sensitivity analysis to find out what would happen if the unconfirmed case with 

insufficient information was assigned as a true incident case in the historical ZVL comparator for 

a total of 3 confirmed cases. The incidence rate became 3.6 with a confidence interval ranging 

from 0.7 to 10.4. That may not seem like a big difference, but following that, the RR risk 

decreased from 3.5 (95% CI 0.3, 47.8) to 2.3 (95% CI 0.2, 20.2) and the risk difference 

decreased from 5.9 per (95% CI -6.0, 17.7) to 4.7 (95% CI -7.4, 16.8). That is not a trivial 

change and illustrates the challenges when working with rare outcomes and small numbers of 

doses administered [1Sejvar et al. Population incidence of Guillain-Barré syndrome: a 

systematic review and meta-analysis. Neuroepidemiology. 2011;36:123-33; 2Using data from 

Shui et al. Guillain-Barré syndrome incidence in a large United States cohort (2000-2009). 

Neuroepidemiology. 2012;39:109-15]. 

To summarize the review of GBS cases in VAERS, there were no EB data mining or PRR 

findings for GBS. After review and adjudication of VAERS reports, a reporting rate of 2.4 cases 

per million RZV doses distributed is estimated.

Regarding the FDA assessment of the risk of GBS following RZV from Medicare data, upon 

detection of the statistical signal for GBS following RZV in the VSD RCA in the fall of 2018, CDC 

consulted with FDA on the possibility of additional analyses in other databases. Subsequently, 

FDA in collaboration with CDC and CMS initiated an assessment of risk of GBS following RZV 

in Medicare data. Interim results of an automated ICD-coded analysis are now available, and 

additional work to refine the analysis is in progress. 

FDA focused on replicating the signaling of the VSD analysis in a cohort comparison of the 

post-vaccination GBS rate between a vaccinated RZV population and a historical vaccinated 

ZVL population. Vaccinations are identified using National Drug Codes (NDCs) in Part D. The 

RZV vaccination window is October 2017 through December 2018 and the ZVL vaccination 

window is October 2012 through September 2017. The population included individuals who 

aged into Medicare during those periods, so they already were 65 years of age or older. They 

had to have continuous enrollment in Medicare Parts A, B, and D for 365 days prior to 

vaccination to ensure that there was no GBS in the 365 days prior to the vaccination date. The 

risk window was 1 to 42 days post-vaccination. The outcome was an ICD-coded inpatient GBS 

diagnosis.

For the RZV vaccinated cohort, there were 15 ICD-coded GBS cases, 1.3 million eligible doses, 

and 514.9 total person time. That comes out to an outcome rate of 0.029/100,000 person-days. 

For the ZVL vaccinated cohort, there were 9 ICD-coded GBS cases, 1.8 million eligible doses, 

and 753.4 total person time. That is an outcome rate of 0.012/100,000 person-days. The RR is 

simply the GBS rate in the RZV vaccinated cohort divided by the GBS rate in the ZVL 

vaccinated cohort. After adjusting for age and sex, the RR was 2.34 (1.01, 5.41). Looking at 

outcome per million doses, the outcome rate for the RZV cohort is 11.38/million doses 

administered and for the ZVL cohort is 4.95/million doses administered. The RR was the same, 

2.34 (1.01, 5.41), but now this is put into an attributable risk per million doses. Adjusted for age 

and sex, that is 6.54 (-0.11, 13.9) per million doses administered.

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In summary, the interim results of the FDA cohort comparison of post-vaccination GBS rate 

between the vaccinated RZV population and historical ZVL population showed an elevated 

adjusted RR of 2.34 (95% CI 1.01, 5.41). These results should be interpreted with caution. This 

is an automated analysis using ICD-coded GBS diagnoses. Chart review/confirmation of cases 

is pending. Current versus historical comparisons are subject to potential confounding and 

require adjustments, which are in progress. A chart confirmed, self-controlled analysis is 

planned, which will control for many potential confounders of historical comparator designs. 

Regarding selected secondary outcomes and secondary analyses, a descriptive analyses for 

lower priority outcomes in the historical comparator ZVL design shows a RR was <1 for

hemorrhagic stroke (0.48) gout (0.84), pneumonia (0.65), and zoster ocular (0.63). RR was ~1 

for non-hemorrhagic stroke (0.95), local reactions (0.96), uveitis/retinitis (0.89), and urgent 

care/emergency department visit (0.90). RR was >1 for systemic reactions (1.21), non-specific 

AE (1.23), and keratitis (1.15). Looking at the well-visit comparators 50+ years of age during the

RZV uptake period (N=1,415,492), all high priority outcomes had a RR <1.0 except GBS, which 

was slightly elevated with a RR of 1.86 (5 observed versus 2.7 expected events). Looking at 

other non-influenza vaccine recipient comparators 50+ years of age and older during RZV 

uptake (N=518,115) for the high priority outcomes, RR was <1.0 except for GBS with a RR of 

1.53 (5 observed versus 3.3 expected events). 

In conclusion, this is still the initial uptake period for RZV and it is early in the post-licensure 

monitoring process considering constraints on supply. There have been 11.89 million RZV 

doses distributed for the US market through March 2019. There were 211,109 RZV doses 

included in the 7th of 18 VSD RCA analyses covering the period January through December 

2018, with outcome monitored through April 2019 and 1,318,004 RZV doses included in the 

FDA Medicare data analysis. For the past influenza season, 5.4 million doses were 

administered in the VSD.

There have been no concerning patterns or findings of disproportional reporting for adverse 

health events in VAERS. Statistical signals detected for Bell’s Palsy and GBS in VSD RCA in 

automated analyses. An elevated RR for GBS was detected in the FDA cohort analysis in 

Medicare data using automated analysis. The statistical signal for Bell’s Palsy in the VSD RCA 

is not consistent across comparators. Currently the RR in the primary analysis is 1.31. However, 

the RR are <1 in the secondary concurrent comparator analysis.

The assessment of the statistical signal for GBS in VSD included chart review of all potential 

GBS cases identified by ICD codes in the current RZV and historical ZVL recipients. The chart 

confirmed RR is 3.5 (95% CI 0.3, 47.8) based on 2 RZV and 2 ZVL confirmed cases. The risk

difference is 5.9 per 100,000 person years (95% CI -6.0, 17.7). The interim results of the FDA 

cohort comparison of post-vaccination GBS rates between the vaccinated RZV population and 

historical ZVL population using ICD-coded cases showed elevated rate ratio of 2.34 (1.01, 5.41)

and an attributable risk of 6.54 (-0.11, 13.9) additional cases per million doses administered.

Additional analysis and chart review/confirmation are pending for the FDA study.

Regarding next steps, the safety profile of RZV is generally consistent with pre-licensure clinical 

trial data. Two systems have detected an increased risk for GBS; however, the numbers are 

small in VSD and chart reviews are pending in FDA Medicare analysis. CDC will continue to 

monitor GBS and Bell’s Palsy in VSD. FDA is in the process of accessing charts to review GBS 

cases in the Medicare cohort analysis, and will consider doing a chart confirmed self-controlled 

analysis to further assess risk of GBS following RZV. Dr. Shimabukuro emphasized that CDC 

believes the take-home message is that the initial safety monitoring data so far are insufficient 

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to conclude that a safety problem exists for GBS, but further evaluation and continued vigilance 

are warranted. 

Discussion Points

Regarding next steps, Dr. Lee said she realized that the numbers probably would be incredibly 

small in the concurrent analysis (comparison groups) but wondered when data would be 

forthcoming from that. She also wondered about calling out seasonality of GBS as one of the 

potential confounders, and whether there were any odd shapes in the curve for RZV vaccination 

given the sudden uptick and the supply issues and whether that would be worth considering. 

The uptick curve looked fairly stable throughout, so probably there was not any in the VSD, but 

she was curious about whether there was any difference in Medicare.

Dr. Shimabukuro indicated that they plan to present the results of the primary and secondary 

analyses as requested by the WG and CDC. He was not aware of any seasonality for uptake of 

RZV in either VSD or Medicare. Uptake has been constrained by supply, so it is probably not 

the normal uptake that would occur if supply was meeting demand.

Given that influenza can increase GBS rates, Dr. Hunter wondered whether the cases or rates 

between cases and non-cases through the chart review showed more or less influenza 

diagnosed.

Dr. Shimabukuro replied that they have not looked for influenza disease as part of this analysis.

Dr. Moore suggested that it might be beneficial for the purposes of the discussion to hear the 

presentation from Dr. Dooling on the WG’s interpretation of the results before engaging in a 

more in-depth conversation about safety.

Dr. Friedland (GSK) emphasized that GSK’s top priority is patient safety and they are committed 

to monitoring and ensuring the safety of all of their vaccines, which includes SHINGRIX. As 

indicated in the presentation, the ongoing safety monitoring data to date are insufficient to 

conclude that a safety problem exists for GBS or Bell’s Palsy. Continued vigilance and further 

evaluation are warranted. GSK will continue to monitor reports of GBS and Bell’s Palsy following 

vaccination with SHINGRIX through their enhanced pharmacovigilance, and they will be 

evaluating any new information that becomes available. In addition, incident cases of GBS will 

be measured in the objectives of GSK’s planned post-marketing targeted safety studies. In 

summary, GSK remains confident in the favorable benefit-risk ratio profile of SHINGRIX for the 

prevention of herpes zoster and will continue to work closely with CDC and FDA to actively 

monitor the safety of SHINGRIX. 

Summary of HZ WG Interpretation of RZV Safety Data

Dr. Kathleen Dooling MD MPH

Herpes Zoster Work Group Liaison

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Dooling expressed the WG’s gratitude to the ISO, VSD, and FDA for their contributions 

toward monitoring the safety of RZV. In terms of the WG’s interpretation of the RZV safety data, 

approximately 12 million doses of RZV have been distributed in the US since the vaccine was 

licensed. Thus far, the most common reports have involved non-serious reactogenicity-like 

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symptoms consistent with findings from the RCTs. The RCA has yielded preliminary statistical 

signals for two conditions, Bell’s Palsy and GBS. She presented a summary of the data the WG 

felt was key in interpreting these signals, organized in a framework of increased certainty of 

classification and association starting with the events reported in VAERS, followed by data from 

ICD-9 and ICD-10 automated sources, and finally those cases validated by vaccine safety 

experts and known to have occurred in the 42 days following vaccination.

In terms of Bell’s Palsy following RZV, there were no signals in VAERS. With respect to 

administrative data cases, there was an increased risk when compared to historical ZVL in the 

VSD. However, there was no increased risk when concurrent comparator groups were used. 

Upon medical chart review of those administrative cases of Bell’s Palsy, only 15 of 36 (42%) 

were actually validated as true incident cases. Regarding the investigation of GBS following 

RZV, there were no signals in VAERS. With respect to administrative cases, an increased RR 

was observed in both VSD and Medicare based on historical rates following VZL. However, the 

RR was lower when concurrent comparator groups were used in VSD. Upon medical chart 

review of the administrative cases of GBS, two cases were validated as true incident cases in 

the RZV group and two in the ZVL group. This resulted in a risk difference of between 4.7 to 5.9 

cases per 100,000 person years. That represents an increased risk relative to ZVL as well as 

baseline rates from the literature. However, due to small numbers, the confidence intervals are 

very large.

In summary, GBS is rare and interpretation of elevated risk of GBS is uncertain given only 2 

validated cases in the RZV and the ZVL groups. Due to wide confidence intervals that overlap 

baseline rates, current data are insufficient to determine if a safety problem exists. The HZ WG 

members agree that there is insufficient evidence at this time to support a change in policy or 

practice and agree with the proposed next steps to: 1) continue enhanced monitoring and 

clinical case review of Bell’s Palsy and GBS reports following RZV in VAERS; 2) continue to 

track and chart validated cases of Bell’s Palsy and GBS in BSD; and 3) chart validated GBS 

cases in Medicare and pursue self-controlled analytic options.

Discussion Points

Dr. Bernstein wondered whether there are any data regarding the use of a novel adjuvant and 

GBS or Bell’s Palsy, or studies of just the AS01B adjuvant itself.

Dr. Shimabukuro indicated that none of the cases in the VSD had co-administration of a vaccine 

that had a novel adjuvant, though he would have to check the VAERS reports. In the VAERS 

reports, RZV was administered alone in over 90% of the Bell’s Palsy and GBS cases. Based on 

the reports in general, RZV tends to be administered alone. There have been several reports of 

AEs following RZV co-administered with FLUADTM, but these were non-serious injection site 

reactions. In terms of the adjuvant itself, he deferred to the manufacturer.

Dr. Friedland (GSK) indicated that in the clinical trials leading to licensure of SHINGRIX, there 

was no increased risk of GBS or Bell’s Palsy noted.

Dr. Moore commented that the WG feels that it is very important to be transparent in displaying 

the process of how vaccine safety evaluation works. Examining vaccine safety in an older adult 

population in which there are many underlying issues is more complicated than in young healthy 

children with very few background health issues. The WG also acknowledges that although 

numbers were presented that may appear quite precise, it is very difficult to study GBS given 

the seasonality, different rates based on age and other factors, et cetera. It is possible as 

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additional refinements to the studies are done, there may be a more accurate picture that has 

different numbers than the numbers presented during this session. She cautioned everyone to 

look at the trends, but not get fixated on any particular numbers because important adjustments 

to address confounding that has not yet been addressed might result in a different look to the 

final results as there is more information and better analysis. The WG wanted to share the 

process to let people know where they are, because it could take time before those analyses 

are completed.

Regarding seasonality, Dr. Dooling explained that the analysis presented during this session 

were based on doses given in 2018. The vaccine did not become largely available until March 

and April of 2018. Therefore, the doses contained in the analyses presented cover only part of a 

calendar year through December 23, 2018.

Dr. Lee echoed what Dr. Moore said about being grateful to ISO for the incredible vaccine 

safety system that has been developed and enhancing their ability to monitor any AEs that 

occur in near-real time. That is a major testament to the fact that they are taking a dynamic look 

over time. She also expressed appreciation for the transparency and willingness to think 

critically with ACIP about feedback and how these analyses can be made better. The analyses 

to date have been excellent.

Henry Bernstein, MD, MHCM

Chair, ACIP Pertussis Vaccines WG

Professor of Pediatrics

Zucker School of Medicine at Hofstra/Northwell

Cohen Children’s Medical Center

New Hyde Park, New York

Dr. Bernstein indicated that during this session, the Pertussis Vaccines WG wanted to address 

the following three questions:

1) Should the current recommendation that non-pregnant adults receive a single lifetime dose 

of Tdap with Td boosters every 10 years be changed to allow any Td-containing vaccine 

(Tdap or Td) to be used for the decennial Td booster? 

2) Should any Td-containing vaccine (Tdap or Td) be allowed for tetanus prophylaxis in the 

setting of wound management?

3) Should the catch-up immunization schedule for Tdap/Td be changed for those ≥7 years of 

age? 

The first two questions represent the WG’s initial terms of reference, while the third arose in the 

midst of carrying out the first two.

Pertussis Vaccines

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In terms of what prompted these questions, the most important issue was the FDA label change 

to Sanofi’s Tdap product Adacel®. The routine booster allows for a second dose of Adacel® to 

be administered ≥8 years after the first dose of Tdap. In addition, Adacel® can be used in wound 

management. A booster dose of Adacel® may be administered if it has been ≥5 years since the 

previous receipt of a tetanus toxoid-containing vaccine. There is not change to GSK’s Tdap 

product BoostrixTM. There is clear evidence that repeat Tdap vaccination is widespread. 

In terms of the current ACIP Tdap recommendations for non-pregnant adolescents and adults, 

since 2005, ACIP has recommended a single Tdap dose in adolescents and adults ≥11 years of 

age. There is no minimum interval since the last Td vaccine before Tdap can be given. At this 

time, only pregnant women are recommended to receive more than one dose of Tdap, with a 

dose being given during every pregnancy. It is important to note that this is an off-label 

recommendation that has been in place since 2012. Part of the current guidance to maintain 

protection against tetanus and diphtheria in those who have received a single dose of Tdap is to 

receive a decennial Td booster dose. This may be indicated for wound management if it has 

been ≥5 years since the previous receipt of a tetanus toxoid-containing vaccine. Per the WG’s 

terms of reference, they will be discussing whether this language should be changed to allow 

any Td-containing vaccine (Td or Tdap) to be used for the decennial Td booster or for wound 

management. Regarding the third question, the Tdap primary immunization schedule for those

≥7 years of age who have not been fully immunized is 1 dose of Tdap as part of the catch-up 

series that preferably should be given as the first dose. If additional doses are needed, Td is 

supposed to be given. It is important to recognize that the catch-up schedule includes pregnant 

women [Liang JL, et al. Prevention of Pertussis, Tetanus, and Diphtheria with Vaccines in the 

United States: Recommendations of the Advisory Committee on Immunization Practices (ACIP). 

MMWR Recomm Rep. 2018 Apr 27;67(2):1-44]. 

EtR Framework for the use of Tdap for Decennial Td Booster, 

Tetanus Wound Prophylaxis, and the Catch-Up Immunization Schedule

Fiona Havers, MD, MHS

Lead, Pertussis Vaccines Work Group 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Havers began by going over the EtR Framework for the two main policy questions that focus 

on the use of Tdap for the decennial Td booster and for tetanus prophylaxis, beginning with a 

discussion of benefits and harms. As discussed in the October ACIP meeting, the previous 

Pertussis Vaccines WG assessed in detail whether to preferentially recommend that Tdap 

replace Td. The present WG reviewed these considerations, but in general, focused on 

programmatic issues, including the impact that changing the recommendations would have on 

clinical providers. Because the WG’s focus was on programmatic considerations, they did not 

conduct a detailed GRADE analysis of the benefits and harms of potential changes to 

recommendations. In addition, she reviewed the evidence for other elements of the EtR 

Framework (values, preferences, acceptability and feasibility, resource use), the WG’s 

interpretation, and the catch-up immunization schedule. 

In terms of benefits and harms, benefits to providers include ease and flexibility. It is often 

challenging to determine whether a patient has previously received Tdap, and it is cumbersome 

to have to stock both Td and Tdap vaccines. The WG concluded that there are benefits to giving 

providers the flexibility to administer either Td or Tdap.

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There was considerable uncertainty about the potential benefits that result from the impact of 

repeat Tdap vaccination on pertussis prevention and control. There is evidence that a second 

dose of Tdap is immunogenic, although immunogenicity data after receipt of more than 2 doses 

are lacking. In addition, the duration of protection is uncertain, and may vary by population 

group. There is some evidence of short duration of protection in persons who were given 

acellular pertussis vaccines for their childhood series, but there is a lack of data on duration of 

protection among those primed with whole cell pertussis vaccines in childhood. In addition, 

Tdap vaccines have an uncertain role in the prevention of transmission and herd immunity.

While several WG members felt that Tdap should be preferentially recommended to replace Td, 

the majority of WG members felt that there was insufficient evidence of benefits in pertussis 

control to recommend that Tdap replace Td for all decennial boosters.

The WG also looked at whether recommendations for healthcare personnel (HCP) should be 

different than for the general population. This also had been reviewed by the previous ACIP 

WG. While pertussis transmission has been documented in healthcare settings, there are 

insufficient data that HCP are at increased risk for pertussis infection. In addition, there is a lack 

of strong evidence that additional Tdap doses for HCP would be beneficial for pertussis control 

in healthcare settings. While several WG members felt that Tdap should be preferentially 

recommended to replace Td for HCP, the majority of WG members felt there was insufficient 

evidence of benefits in pertussis control to make recommendations for healthcare personnel 

that are different than those for the general population.

Regarding whether there are any potential harms, the safety data of a second Tdap vaccination 

were reviewed by the previous WG, and more recent data were presented during the October 

2018 ACIP meeting. While the WG acknowledged that there were a number of studies that 

examined the safety of a second Tdap vaccination, there were few that looked at more than 2 

doses. Nevertheless, the WG concluded that based on the evidence available, there were no 

substantive safety concerns in allowing Tdap to be used for the decennial booster or for tetanus 

prophylaxis in the setting of wound management. The WG concluded that, in general, the 

benefits to implementing the recommendation changes outweigh harms.

Moving on to other elements of the EtR Framework, the WG looked at evidence indicating 

whether patients and providers value or have a preference for repeat Tdap vaccination. There 

have been no studies specifically asking the preferences of stakeholders, which the WG defined 

as the general adult population, as well as providers and immunization programs. However, the 

proposed recommendation does not require any additional vaccine doses, likely making it 

acceptable to patients. There also is evidence indicating that repeat Tdap vaccination is already 

a widespread practice, indicating that providers may prefer using Tdap in place of Td.

In terms of the public sector purchases for adult doses of Td and Tdap for the 7 years from 

2011-2017, in any given year Tdap purchases have been at least 10-fold more than Td 

purchases1. The WG also explored other data sources for evidence of this, including a study by 

the VSD that included almost 69,000 persons who had received Tdap and then later received 

another Td-containing vaccine. Among these patients, 89% received Tdap for their second 

vaccine, while only 11% received Td. This is confirmed by information from a large database of 

insurance claims, in which Tdap claims outnumbered Td claims by 11 to 12. Given these data, it 

is likely that giving Tdap in place of Td is already widespread despite the fact that it is not 

currently recommended by ACIP and in clinical practice it is still an off-label use. The WG

concluded that this likely indicates that allowing either Tdap or Td to be used would be 

acceptable and feasible for stakeholders and may be preferred by providers [1Courtesy CDC 

Immunization Services Division, Vaccine Supply and Assurance Branch, Data Team; 2Jackson 

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ML, et al. Safety of repeated doses of tetanus toxoid, reduced diphtheria toxoid, and acellular 

pertussis vaccine in adults and adolescents. Pharmacoepidemiol Drug Saf 2018 Aug;27(8):921-

925]. 

Regarding resource use, Tdap is more expensive than Td. This table shows two different 

sources of cost data: 

The top half of the above table shows data from the CDC vaccine price list, with the cost per 

dose for the generic Td compared with the two Tdap products. The incremental cost of Tdap 

over Td was approximately $11 from this data source. The bottom part of the table shows 

claims data from commercially insured persons. In these data, the median cost for Tdap was 

approximately $22 more than for Td.

Regarding the question of resource use and whether allowing either Tdap or Td to be used in 

place of Td is a reasonable and efficient allocation of resources, the WG did reviewed pricing of 

the two types vaccines and also economic impact analyses, including a detailed review of an 

internal CDC analysis. However, the relevance of economic data to this issue is questionable if 

providers are already giving multiple Tdap doses. Indeed, for all economic analyses available, 

there is considerable uncertainty for a number of key parameters, particularly pertussis 

incidence estimates, which vary widely. Pertussis is underdiagnosed and likely underreported, 

and there is a lack of reliable estimates of disease burden, particularly in adults. Estimates are 

also uncertain for initial vaccine effectiveness, duration of protection, and other parameters. In 

addition, no analyses of the economic impact accounted for cost savings resulting from 

providers only carrying one vaccine instead of two and the impact on pertussis epidemiology 

resulting from the fact that multiple doses of Tdap were likely already being given. After 

evaluating the economic evidence, the WG concluded that the economic impact analyses did 

not drive their decision-making process for these particular programmatic questions.

Regarding whether any Td-containing vaccine (Tdap or Td) should be allowed for use for the 

decennial Td booster and tetanus prophylaxis in the setting of wound management, the WG

group concluded that allowing this recommendation gave increased flexibility to providers and 

that there may be some additional benefit for pertussis control, but that there was not enough 

evidence to preferentially recommend Tdap over Td. They concluded that there were no 

substantive safety concerns, and given this, the benefits of the recommendation change 

outweighs potential harms. The WG also concluded that providers value flexibility, and that 

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there is evidence that Tdap has largely replaced Td regardless of current recommendations, 

which indicates that the change would be valued by stakeholders and that it is likely acceptable 

and feasible. Although Tdap is more expensive than Td, economic analyses had limited utility. 

Given that the change has been widely implemented already, regardless of the higher cost and 

the uncertainty of key parameters in the various economic models, economic impact was not a 

major consideration for the WG group for these questions.

While the WG was discussing these questions for the decennial booster and wound 

management, one further question arose, “Should any Td-containing vaccine (Tdap or Td) be 

allowed for additional catch-up doses for those person ≥7 years old with incomplete or unknown 

vaccine history?” As Dr. Bernstein mentioned in his introduction, the current catch-up schedule 

consists of three doses, one Tdap preferably for the first dose and two subsequent Td doses. 

One policy option discussed was to make no change to the current catch up schedule. The WG

discussed whether the catch-up immunization schedule should be a dose of Tdap followed by 

two doses of either Tdap or Td, which would allow providers flexibility in choosing which vaccine 

to give for the additional doses. They also discussed whether more than 1 dose of Tdap should 

be preferentially recommended over Td for either 1 or both of the additional doses. The majority 

of the WG agreed with a permissive change in the recommendations, which states that at least 

one dose of the catch-up schedule should be Tdap, but that the additional doses could be either 

Tdap or Td. The rationale for this was similar to that for the two main questions already 

addressed, in that there were benefits to providers in having more flexibility and ease of use. 

There also may be some additional benefit to having more than one pertussis-containing 

vaccine for pertussis protection in previously unimmunized persons, but there was not enough 

evidence to preferentially recommend Tdap over Td. In addition, particularly if the other 

recommendations are put into place and result in a decrease in the availability of Td, increased 

flexibility for providers would be helpful.

One final nuance was noted. The current catch-up schedule is the same for pregnant women as 

for the general population, and any changes would therefore also apply to pregnant women.

Previously unimmunized pregnant women may require two doses of a tetanus-toxoid containing 

vaccine to prevent obstetric and neonatal tetanus. Data are lacking on the safety of multiple 

doses of Tdap during a single pregnancy. There are some data from pregnancy registries of 

patients who inadvertently received more than 1 dose during a single pregnancy, and there 

have been no concerning safety signals for this or for women who receive closely-spaced Tdap 

vaccinations in different pregnancies. Thus, the WG concluded that recommendations for catchup immunization in pregnancy should be similar to those for the general population. 

If the changes discussed in this presentation are adopted by ACIP, there are several situations 

in which recommendations would be off-label. This table shows the two licensed Tdap products

and a summary of their FDA approved indications, usage, and administration in the second 

column. The last three columns indicate where use of these two products would be off-label if 

recommendations were changed for the decennial Td booster, tetanus prophylaxis in the setting 

of wound management, and the catch-up immunization series: 

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Off-label indications based on age have not changed. New off-label indications for Adacel®

would include any additional routine or catch-up Td dose beyond a second dose administered 

≥8 years from a first Tdap dose, if not given for wound prophylaxis within the specified 

guidance. For BoostrixTM, any additional doses of BoostrixTM beyond the single licensed dose 

would be off label. The WG did not find any reason to distinguish between these two products in 

making their recommendations.

In summary, for the three questions of whether either Tdap or Td should be allowed to be used 

for the decennial Td booster, for tetanus prophylaxis in the setting of wound management, or for 

additional doses of the catch-up immunization schedule for persons aged 7 years or older, the 

work group is in favor of these interventions.

Discussion Points

Dr. Walter inquired as to how much data there are on repeat short-term administration of Tdap, 

particularly with regard to safety.

Dr. Havers replied that the article she included was a study conducted on BoostrixTM that 

examined a 0-, 1-, and 6-month catch-up schedule comparing Td and Tdap. There were no 

concerning safety signals in that study. Other than that, she did not think there were a lot of 

other data.

Referring to page 18 of the binder provided to ACIP members, the Policy Option for Adolescent 

and Adult Series for Those with Incomplete or Unknown Vaccine History, it appeared to Ms. 

McNally that with item 2 in the WG recommendation it would be possible that Tdap could be 

given 3 times. She also observed that slide 7 indicated that data are lacking on the safety of 2 or 

more Tdap doses. Therefore, she wondered whether safety data potentially would be 

forthcoming. 

Dr. Havers clarified that there are a number of studies pertaining to safety data, many of which 

were presented during the October 2018 ACIP meeting, on 2 doses of Tdap. So, repeat Tdap 

vaccination has been studied. There have not been many studies on more than 2 doses, but 

there have not been any concerning safety signals in those studies. There is the one study 

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mentioned that had 3 closely spaced doses of Tdap, but there are not a lot of other studies 

assessing more than 2 doses.

Dr. Messonnier indicated that this could be reviewed during the next ACIP meeting in October 

2019. Ms. McNally expressed appreciation for this.

Ms. Stinchfield (NAPNAP) inquired as to whether there are any data on Tdap as a primary 

series. When they discussed Tdap initially, effectiveness was based on a primary series of 

DTaP. She also observed that tetanus is state reportable to CDC, but that the Children’s 

Hospitals and Clinics of Minnesota ED is seeing an emergence of refusal for Td or Tdap for 

wound care. Based on a report she read the day before, there are 3 children in Italy in the 

intensive care unit (ICU) with tetanus. This seems like a worrisome trend that should be tracked.

Dr. Havers indicated that there was the one study she mentioned comparing Td versus Tdap as 

the primary immunization series that was conducted in Germany, which assessed a cohort of 

adults who either had not received any vaccine for at least 20 years or who had an unknown 

vaccination history. Td and Tdap were immunogenically equal for the tetanus and diphtheria 

components and there was some antibody boost with the pertussis component.

Dr. Hariri (SME, Team Lead for the Epidemiology Team) pointed out that Tdap was licensed for 

adolescent use. The DTaP vaccine is the only vaccine that is licensed for use as the primary 

series in children.

Dr. Havers added that Tdap is used for a primary series for those ≥7 years of age who are 

receiving a catch-up schedule or they were un-immunized. However, there are not much data 

on this.

Centers for Disease Control and Prevention (CDC)

Dr. Messonnier reported that a lot of CDC attention for the past 3 months has been focused on 

responding to the ongoing measles outbreaks. They believe that those outbreaks are a signal 

that more work needs to be done to prevent vaccine-preventable diseases and vaccinepreventable disease outbreaks across the US. CDC and its partners are working to protect 

Americans against measles and other vaccine-preventable diseases through a larger strategy 

that they will be socializing and rolling out in the next couple of months. There are 3 main areas 

of focus. The first is vaccine access, which remains a perennial issue despite the availability 

through the VFC Program. Children of lower economic status or without insurance still have 

lower vaccination coverage, an issue which needs to be addressed. The second is the measles 

outbreaks occurring this year, which are primarily among pockets of under-vaccination that exist 

in the US. Of the cases, 90% are associated with those communities and those communities 

are at higher risk for spread of measles. It is necessary to do a better job of identifying those 

communities in advance and working with local state health departments and frontline clinicians 

to intercede. The third is the spread of misinformation and myths about vaccines across the US. 

Although overall confidence in vaccines and overall vaccine coverage remain high, the spread 

of misinformation continues to be a threat to undermining public confidence in vaccines. 

Certainly, CDC will focus on making sure that scientifically valid information is easily available 

and accessible to the public through all means possible. In addition, CDC is participating in 

Agency Updates

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Crimson Contagion, which is an HHS exercise series focused on pandemic influenza with HHS 

as the lead federal agency. This is a series designed to examine information exchange, 

coordination of resources, and policy decisions in a pandemic influenza scenario. In addition to 

the series of exercises, Crimson Contagion culminates in a multi-state, multi-agency functional 

exercise August 13-16, 2019 to examine the local, state, and federal response to an established 

pandemic that is in the acceleration phase of a dynamic response. The belief continues to exist 

that pandemic influenza remains a high risk for the US and globally. These exercises help to 

refine response approaches and enhance preparedness.

Centers for Medicare and Medicaid (CMS)

Ms. Hance reported that the Center for Medicare and Medicaid had its monthly call with its 

Medicaid Quality Partners the previous day. CDC joined the call to share toolkits for measles 

and back-to-school. The primary focus of this conversation was to discuss the importance of 

preparing now for back-to-school immunizations with the goal of increasing immunization rates 

for children enrolled in Medicaid. She expressed CMS’s appreciation for the coordination of their 

CDC colleagues in this call.

Department of Defense (DoD)

Dr. Deussing expressed the Department of Defense’s (DoD’s) appreciation to ACIP and CDC 

for its continued inclusion of the DoD in ACIP meetings and WGs. There have been significant 

and ongoing organizational changes throughout the military health system in relation to the 

National Defense Authorization Acts (NDAAs) of 2017 and 2019. Fortunately, these changes 

have had minimal impact on DoD immunization procurement and delivery. A specific example is 

the YF vaccine. The Immunization Healthcare Branch (IHB) works closely with YF vaccine 

manufacturer and was able to maintain vaccine availability to support worldwide DoD operations 

despite supply constraints. Major lines of effort supporting this success included restricted

administration criteria, site ordering limitations, and active product redistribution. YF vaccine 

redistribution within the DoD during this national shortage from April 2016 through March 2019 

totaled 6574 doses worth over $400,000. Regarding seasonal influenza vaccine, the DoD met 

all immunization targets during the 2018 influenza season, including mandatory vaccination of 

uniformed personnel and HCP. Preparations are underway for the 2019 influenza season, with 

final publication of the seasonal influenza vaccine policy pending. The Pragmatic Assessment of 

Influenza Vaccine Effectiveness in the DoD (PAVED) study completed its first year of enrollment 

with the aim of assessing the clinical effectiveness of licensed influenza vaccines used by the 

DoD. This study group is Co-Chaired by the IHB and the Uniformed Services University (USU) 

Infectious Disease Clinical Research Program (IDCRP). While results are still pending, the 

study group was able to enroll over 1600 participants into the main study at 5 different sites and 

200 of those into the immunogenicity sub-study developed in partnership with the Armed Forces 

Health Surveillance Branch (AFHSB), Naval Health Research Center (NHRC), US Air Force 

School of Aerospace Medicine (USAFSAM), and the FDA. For the upcoming season, the 

PAVED Study Group would like to enroll 13,500 subjects at 11 sites. Educational outreach to 

beneficiaries continues the IHB’s public-facing webpage, online and onsite courses, and toolkits. 

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Department of Veterans Affairs (DVA)

Dr. Kim reported that over 1.8 million veterans enrolled in VA healthcare received free influenza 

vaccines in outpatient settings within VA facilities during FY2018. In addition, VA continued in a 

Regional Partnership Program that resulted in more than 110,000 veterans receiving 

vaccinations paid for by VA during the last influenza season. VA completed updates for its 

Hepatitis A Immunization and Clinical Preventive Services Guidance Statement and Hepatitis B 

Immunization and Clinical Preventive Services Guidance Statement. In those updates, VA 

updated indications for HepA vaccinations to include homeless individuals. In follow-up of this 

update, VA launched a campaign in May 2019 to ensure that homeless veterans enrolled in VA 

healthcare who are not immune and are unvaccinated for HepA and who had risk factors for 

HepB were offered vaccinations as appropriate in their next clinical encounter. As a part of this 

campaign, VA created a surgical dataset to identify homeless veterans who are not immune 

HepA and had not received HepA vaccine. This dataset could be accessed by VA medical 

center staff.

Food and Drug Administration (FDA)

Dr. Fink reported that there has been one vaccine approval since the last ACIP meeting. On 

May 1, 2019 FDA approved DENGVAXIA®, which is a live-attenuated chimeric dengue vaccine 

on a yellow fever (YF) backbone that is indicated for prevention of dengue disease caused by 

serotypes 1, 2, 3, and 4 in individuals 9 through 16 years of age with laboratory-confirmed prior 

dengue infection and living in endemic areas. This indication is precedent-setting for 

preventative vaccines in a number of ways. First, it is a vaccine indicated for secondary 

prevention in individuals who already have been infected at least once with dengue. This is 

because the safety data did not support use for primary prevention in individuals who had never 

previously been infected with dengue. Related to that point, the vaccine is limited for use in 

individuals living in dengue-endemic areas. Finally, this is the first vaccine that FDA has 

approved that requires a laboratory test to identify individuals for whom the vaccine is indicated. 

The Dengue WG will present all of the details about the data that supported the indication and 

the limitations of use during the discussion later in the day. ACIP will have a tough job deciding 

how this vaccine should be used, given that dengue epidemiology is not static and the 

technology available for determining prior dengue infection is evolving.

Health Resources and Services Administration (HRSA)

Dr. Nair provided an update on the National Vaccine Injury Compensation Program (VICP). 

HRSA continues to process an increased number of claims. In Fiscal Year (FY) 2018, there 

were 1248 claims. In that same FY, petitioners were awarded $226 million and attorneys were 

awarded $26.9 million. That includes fees to attorneys for cases that were compensated or 

dismissed, as well as interim fees. For this FY, 709 claims have been filed with the program as 

of May 2019 and petitioners and attorneys have been awarded $154 million. Because of the 

increased number of claims that have been filed with the program in the past three years, there 

is a backlog of 726 claims that are awaiting review by Medical Officers. More data about the 

VICP can be obtained on the HRSA website. 

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Indian Health Service (IHS)

Dr. Weiser reported that IHS continues to advise its clinics and hospitals to update measles 

vaccinations for those who need it, and to be prepared to limit the spread of measles in its 

facilities with careful attention to infection control practices. Since the last ACIP meeting, IHS’s 

2-year old MMR coverage is 87%, which is a slight increase, and its adolescent MMR coverage 

with 2 doses is 96%. The IHS electronic medical record (EMR) system, the Resource and 

Patient Management System (RPMS), is undergoing updates this month and next month. 

Among other things, this will include a new immunization forecaster. They are actively testing 

the immunization forecaster and are working to develop 2-way immunization exchange with 

each of the state in which there are IHS facilities. In the Northwest, there has been great 

support with Tribal Immunization Summits in Idaho and Oregon, and a state-led Assessment, 

Feedback, Incentive and eXchange of information (AFIX) program evaluations in both of those 

states. Dr. Weiser expressed IHS’s gratitude to CDC for its support to address decreased 

childhood immunization rates in Indian Country, particularly in Region 10 that includes Oregon, 

Washington, Idaho, and Alaska through a grant addendum for the Tribal Epidemiology Centers 

(TECs) to focus on patient and provider education. He also expressed IHS’s appreciation for the 

concern that ACIP and the WGs have shown for the health of AI/AN by highlighting the potential 

consequences from recommendations for PCV13 and the new pediatric hexavalent vaccine. 

IHS will continue to monitor developments related to pneumococcal disease. Regarding the 

pediatric hexavalent vaccine, IHS is aware that Merck is pursuing investigator-initiated studies 

of post-dose 1 that could provide evidence needed for a preferential recommendation for AI/AN 

children. 

National Institutes of Health (NIH)

Dr. Beigel provided an update from vaccine-related studies and/or funding opportunities at the 

National Institutes of Health (NIH). Influenza is a high priority for NIH and ACIP. There are 

several awards ACIP should be aware of. There is a multi-center study looking at pediatric 

immune systems and how the initial vaccines and subsequent infections model the immune 

response going forward. There is an additional new universal influenza vaccine candidate that is 

another HA stem underway at the Vaccine Research Center (VRC) intramurally at the clinical 

center at NIH. In terms of STIs, the National Institute of Allergy and Infectious Diseases (NIAID) 

established 4 cooperative research centers with a total of $40 million over 5 years to work on 

STI prevention and vaccines. The expectation is that each of these will have one vaccine 

candidate ready for clinical trials moving forward. Hopefully, this will jump start the STI vaccines. 

There was a recent HepC vaccine study with an adenovirus prime and a boost. Unfortunately, 

that did not show any efficacy. There were some lessons learned about vaccine design in terms 

of clinical trials for HepC. There is a large focus on HepC vaccines moving forward, so hopefully 

this will not be a significant setback. Takeda had a dengue Phase III study, the development of 

which NIAID contributed to significantly. This was a trial of over 20,000 children and adolescents 

living in dengue endemic areas. The highlight is that the vaccine was shown to be efficacious. 

They are looking forward to the scientific community seeing the full dataset to determine 

whether the concerns were different from other dengue virus vaccines.

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National Vaccine Program Office (NVPO) / National Vaccine Advisory Committee (NVAC)

Ms. Ann Aiken reported that on June 10, 2019, the National Vaccine Program Office (NVPO) 

and Office of HIV/AIDS and Infectious Disease Policy (OHAIDP) merged to become the Office 

of Infectious Disease Policy and HIV/AIDS (OIDP). This merger is a larger part of ReImagine 

HHS: Moving Towards a 21st Century Workforce to better align HHS programs, improve 

efficiencies, and build capacity to further the goals of the office. While the name has changed, 

the goals and functions of the program have not. Dr. Beckman is still the Director of OIDP. 

NVAC met earlier in the month during which ADM Brett Giroir delivered a new charge to the 

committee. There were two previous charges given to the committee. The first was helping to 

plan for the updated 3 to 5 year National Vaccine Plan (NVP). This plan will emphasize the 

importance of vaccination across the lifespan and is a merger between the previous NVP and 

another plan done on adult immunization. NVAC was charged with assessing goal relevance, 

proposing new or revised goals, and prioritizing the top three objectives within each NVP goal 

area or proposed goal area poised to make the greatest impact on the US immunization system 

in the next few years. This work was presented and voted on during the last NVAC meeting 

earlier in June. Those materials are available should ACIP members be interested in further 

details. NVAC’s final task to be presented and voted on during the December 19, 2019 NVAC 

meeting will include identifying new stakeholders to engage during plan development and 

writing a report summarizing the committee’s findings. NVAC also was previously charged with 

developing a comprehensive set of recommendations to lay the foundation for an effective 

national strategy for ending immunization disparities in the US to ensure that all Americans have 

an equal opportunity to benefit from live-saving vaccines. A WG has been established to 

develop a report, which will be voted on during the September 26, 2019 NVAC meeting. The 

third charge, which was delivered during the last meeting, called for a follow-on report to the 

NVAC report to the NVAC report that assessed the state of vaccine confidence in 2015. ADM 

Giroir charged the committee to develop a report that outlines determinants of vaccination 

across the lifespan; suggestions for HHS to improve confidence in recommended vaccines; and 

guidance on the utilization of evidence-informed best practices from scientific research fields 

such as anthropology, psychology, and economics; and how to successfully foster vaccine 

confidence through public, provider, and policy interventions. This WG is in the process of being 

established and has deliverables due in September 2020.

Introduction

Emmanuel (Chip) Walter, MD, MPH 

Chair, Influenza Work Group

Professor of Pediatrics, Duke University School of Medicine

Given that this was his last ACIP meeting, Dr. Walter expressed his gratitude to Dr. Grohskopf 

for her invaluable support during his tenure as Chair of this WG, to CDC colleagues, and to 

fellow WG members. He said it had been his honor to Chair this WG, and announced that Dr. 

Atmar would serve as Chair of the Influenza WG moving forward.

Influenza

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Dr. Walter reminded everyone that during the February 2019 ACIP meeting there were 

presentations on the 2018-2019 US influenza season surveillance and preliminary VE

estimates; a presentation from SeqirusTM of results of a Phase III Randomized Observer-Blind 

Comparator-Controlled study of Afluria® Quadrivalent for Children 6 through 59 months of age; 

and a presentation of a Case-Control Study of Inactivated Influenza Vaccine (IIV) and 

Spontaneous Abortion (SA) in the VSD performed during the 2012-13, 2013-14 and 2014-15 

influenza seasons. 

Since February 2010, the WG has engaged in calls about twice a month during which members 

heard 2018-2019 US influenza VE updates; discussed influenza vaccine safety surveillance 

activities; and discussed development of the 2019-2020 influenza vaccine statement. No 

substantial changes in the language were proposed. 

The agenda for this session included the following topics:

 2018-2019 US Surveillance Update

 Interim Estimates of 2018-2019 Seasonal Influenza VE

 End-of-Season Update: 2018-2019 Influenza Vaccine Safety Monitoring

 WG Considerations and Proposed Recommendations for 2019-2020

Influenza Surveillance Update

Lynnette Brammer, MPH

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Ms. Brammer provided a brief update on the 2018-2019 influenza season. Based on data from 

public health laboratories that report their influenza positives to CDC each week, this season 

was remarkable because there were two roughly equal waves of influenza A viruses; first 2009 

(H1N1) viruses and then influenza A(H3N2). Of the viruses reported overall, 96% were influenza 

A and 57% of the influenza A viruses were H1N1. Also of note was that there was very little 

influenza B activity during this season. The switchover from influenza A(H1N1) to A(H3N2) 

occurred during the last week of February.

In terms of the characterization antigenically and genetically of the viruses, the A(H1N1)pdm09 

and influenza B viruses changed very little since February. All 1251 influenza A(H1N1)pdm09 

viruses tested belong to the single genetic group 6B.1A, and 96.1% of those were well-inhibited 

by ferret antisera against the A/Michigan/45/2015 vaccine strain. All 203 B/Yamagata lineage 

viruses belonged to the Y3 clade, and 100% were well-inhibited by ferret antisera against the 

B/Phuket/3073/2013 vaccine strain. There were 3 genetically and antigenically distinct 

B/Victoria subclades cocirculating: V1A (14.7%), V1A.1 (50.4%), and V1A-3Del (34.9%). This 

was a slight increase in the V1A-3Del viruses compared to February. As a reminder, the 2018-

2019 Northern Hemisphere vaccines contained a B/Colorado/6/2017-like V1A.1 virus. 

There was more change among the influenza A(H3N2) viruses. Phylogenetic analysis of the HA 

genes of H3N2 viruses showed co-circulation of multiple clades and subclades. The proportion 

and geographic spread of viruses belonging to clade 3C.3a increased as the season 

progressed. The 3C.3a viruses are antigenically distinguishable from the 3C.2a and 3C.2a1 

viruses including the A/Singapore/INFIMH-16-0019/2016 (3C.2a1), a cell-propagated reference 

virus representing the A(H3N2) component of 2018-2019 Northern Hemisphere influenza 

vaccines. This indicates that this is a drift variant, and circulation of antigenically drifted viruses 

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can impact VE. Looking more closely at the timeline of the 3C.3a viruses, they accounted for 

only 21% of the viruses in December. By the following month, they had become predominant 

and remained the predominant clade throughout the rest of the season.

During the February ACIP meeting, it was noted that the H1N1 and both influenza B 

components for the 2019-2020 influenza season had been selected but the A(H3N2) decision 

had been delayed until the end of March. That selection has been made, with the final 

selections being as follows:

 A/Brisbane/02/2018 (H1N1)pdm09-like virus

 A/Kansas/14/2017 (H3N2)-like virus belonging to the 3C.3a clade

 B/Colorado/06/2017-like virus (B/Victoria/2/87 lineage)

 B/Phuket/3073/2013-like virus (B/Yamagata/16/88 lineage) – quadrivalent only

Moving on to the activity causes by these viruses, influenza-like illness (ILI) was above baseline 

for the longest period that has been observed in the last 10 years. Probably due to the two 

waves of influenza A viruses, ILI was above baseline for 21 weeks, peaking at 5.1% during midFebruary.

The overall rate of hospitalizations due to laboratory-confirmed influenza was 65.1/100,000 

population. The rate was highest among persons ≥65 years of age at 221.4/100,000 population, 

followed by the 50 to 60 year old age group and the 0 to 4 age group. Compared to previous 

influenza seasons, this season was more similar to the 2014-2015 and 2016-2017 influenza 

seasons.

Regarding influenza-associated mortality, the percent pneumonia and influenza deaths 

exceeded the threshold for the first 13 weeks of the year, but only by a very small amount. The 

peak was 7.7% compared to a threshold of 7.3% and 7.2% during the two weeks of 7.7%. Thus, 

there was a very modest increase in influenza- and pneumonia-associated mortality. However, 

119 influenza-associated pediatric deaths have been reported to CDC thus far. This is lower 

than what was observed during the 2017-2018 influenza season, but higher than what has 

occurred in other recent years.

CDC also calculates a severity level for each influenza season. Severity of the 2018-2019 

season was classified as moderate overall and in all age categories. This is calculated using ILI, 

hospitalization, and pneumonia and influenza mortality data. Information on how CDC classifies 

severity is available at https://www.cdc.gov/flu/about/classifies-flu-severity.htm. 

This year for the first time, CDC published interim estimates of influenza burden as the season 

progressed. There were at least 37.4 million influenza illnesses this season overall. Of those, 

17.3 million were medically attended. There were at least 531,000 hospitalizations and at least 

36,400 influenza-associated deaths this season. Comparing the cumulative hospitalization 

burden to previous seasons, this season was similar to the 2012-2013, 2014-2015, and 2016-

2017 seasons.

CDC has received a lot of questions about what is occurring with influenza activity in Australia, 

given that Australia’s influenza season began earlier than typical this year. The number of 

reported influenza positives this season is similar to 2017. Thus far, they have had a mix of 

A(H1N1)pdm09 and A(H3N2) viruses. Most recently, influenza A(H3N2) has been predominant. 

The number of influenza positives reported is getting close to what they saw in 2017, which was 

a severe season for Australia. They had a lot of activity coming into this season. Among the 

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A(H3N2) viruses they are seeing, the predominant clade there is 3C.2a1b viruses rather than

3C.3a. They have seen 3C.3a viruses, but these account for only about 5% of the A(H3N2) 

viruses.

In summary, the severity of the 2018-2019 influenza season was classified as moderate both 

overall and for all age groups. The season was notable for 2 waves of influenza A viruses of 

similar magnitude, an influenza A(H1N1)pdm09 wave followed by an H3N2 wave. The majority 

of H3N2 viruses belonged to the 3C.3a genetic group, which is antigenically distinct from the 

3C.2a genetic group. The recommended H3N2 component for the 2019-2020 Northern 

Hemisphere vaccine is an A/Kansas/14/2017-like virus, which belongs to genetic group 3C.3a. 

Discussion Points

Dr. Ault inquired as to whether there is a way to assess pregnant women with regard to 

influenza severity.

Ms. Brammer replied that the surveillance, virologic, ILI, and mortality data do not have this for 

pregnant women. They do assess pregnant women in the hospitalization data, but there are not 

enough to make a severity estimate for that individual group.

Dr. Bernstein inquired as to how the early influenza season onset in Australia predicts the US 

season onset or how it relates.

Ms. Brammer indicated that some years, the US has a season similar to Australia’s and some 

years not. For example, Australia had a bad year in 2017 and so did the US. CDC was hopeful 

last year that because Australia had a very mild year, the US would as well. However, that did 

not happen. CDC watches Australia very carefully because it is important to understand what 

viruses they are seeing and the impact, but as far as being able to make a prediction, it does not 

necessarily tell them anything definitive.

Dr. Maldonado (AAP) noted that Latin America also had an early onset this season of H3N2 as 

well, and inquired about the genotype of those strains.

Ms. Brammer replied that Latin American also is seeing a mix among their H3N2 viruses, with a 

little more 3C.3a viruses.

Dr. Schaffner (NFID) called attention to Ms. Brammer’s infographic showing the impact of 

influenza, which clearly illustrates that influenza is bad. A follow-up infographic is needed to 

show how the use of vaccines mitigated each of the impacts in order to promote vaccination, 

which he encouraged CDC to provide as quickly as possible each year.

Dr. Duchin (IDSA) inquired as to whether Ms. Brammer could characterize how well the vaccine 

strain antibodies performed in the context of the H3N2 virus.

Ms. Brammer indicated that 73% of the viruses this season were 3C.3a viruses, and the 

majority of those viruses react low using ferret antisera against that virus. Antigenically, it can be 

expected that roughly that proportion will be low.

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Preliminary Estimates of 2018-19 Seasonal Influenza VE 

Against Medically Attended Influenza from Three US Networks

Brendan Flannery, PhD 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Flannery updated ACIP on the work that is being done with 3 networks to prove VE for the 

ambulatory and inpatient settings: US Flu VE Network, Hospitalized Adult Influenza Vaccine

Effectiveness Network (HAIVEN), and New Vaccine Surveillance Network (NVSN). US Flu VE 

Network includes ambulatory patients 6 months of age and older and began in 2004 with 

studies at Marshfield Clinic Research Institute in Wisconsin. It expanded to 4 sites in 2008 and 

the following 5 sites in the US have been conducting the US Flu VE Network studies since 

2011: Kaiser Permanente Washington, Marshfield Clinic Research Institute, University of 

Michigan, University of Pittsburgh, and Baylor Scott and White Health. HAIVEN is an inpatient 

adult network that includes 4 sites, 3 of which are also involved in the US Flue VE Network: 

Baylor Scott and White Health, University of Michigan, University of Pittsburgh, and Vanderbilt 

University. NSVN, conducted in collaboration with CDC’s Division of Viral Disease (DVD), 

includes inpatients 6 months through 17 years of age from 7 sites: Seattle Children’s, University 

of Rochester, Children’s Mercy Hospital, Children’s Hospital of Pittsburgh, Cincinnati Children’s, 

Vanderbilt University, and Texas Children’s. Both of the inpatient networks started around the 

2015-2016 season for influenza VE. 

This presentation of preliminary estimates for the June ACIP meeting represents a lot of work 

on the part of the HAIVEN and NVSN investigators for the inpatient networks to provide 

preliminary estimates for the 2018-2019 season. In terms of the methods, the US Flu VE 

network is an ambulatory network that includes patients 6 months of age and older. The acute 

respiratory surveillance (ARI) definition for this network is essentially cough and other 

respiratory illness symptoms of ≤7 days in duration for the collection of specimens for 

enrollment. The HAIVEN network is the inpatient adult network comprised of patients ≥18 years

of age. The definition of ARI includes a variety of respiratory symptoms and the collection period 

is within ≤10 days for specimens for inclusion. The NVSN is the inpatient network that includes 

children 6 months to 17 years of age. The ARI definition includes fever and other respiratory 

illness symptoms, and the collection period is ≤10 for enrollment for the collection of specimens.

All three of these networks use a test-negative design that compares the odds of laboratoryconfirmed influenza among vaccinated versus unvaccinated patients. Vaccination status for 

these analyses is done with identification of receipt of ≥1 dose for children 6 months through 8 

years with of any of the 2018-2019 seasonal influenza vaccine at least 14 days prior to illness 

onset. The sources include medical records, immunization registries, and self-report in the 

ambulatory setting. The inpatient estimates are based at this time on self-report, but will be 

updated with final vaccination status. VE is calculated as 1 – the adjusted odds ratio (OR) x 

100%. Adjustment is made for potential confounding variables including study site, age, and

calendar time for the different networks.

This table shows the period of enrollment, the total number enrolled for each network, and the 

percent positivity. The pie charts show the distribution of virus subtypes:

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There was very little influenza B in the three networks, so there are no estimates for influenza B. 

However, there was enough H1 and H3 for each of the networks to provide estimates for those. 

It is important to note that the percent positivity in inpatient networks is expected to be lower 

using the sensitive case definition than the percent positivity in the ambulatory network, which 

was about 28%. The other fact to note is that there has been a major effort to sequence a lot of 

the viruses. There are sequences for all of the viruses that have been identified and sent to 

CDC. Specifically, 92% (721/786) of the H3 viruses sequenced in US Flu VE were 3C.3a and 

91% (85/93) of the H3 viruses sequenced in HAIVEN were 3C.3a. For the three networks, there 

is a predominance of the antigenically different 3C.3a viruses this season. That is reflected in 

the VE estimates.

Beginning with the ambulatory network, the VE Network data were presented through the 

beginning of February for the interim report. At the beginning part of the season, there was a 

low percentage positivity and those were predominantly H1N1 viruses in the cases. The 

increase in percent positivity after the interim report was associated with H3 activity at all 

enrollment sites and a large increase in the percentage positive overall for influenza. In terms of 

overall VE in the outpatient network, there were 2795 cases and 7246 controls. The percent 

positivity among the vaccinated was 48% and among the controls was 56%. That results in an 

adjusted OR in VE estimate of 29% (CI: 21% to 35%). Some difference was observed in overall 

effectiveness by age group. The highest VE was seen in the group 6 months through 8 years of 

age at 49% (38,58). There was only one other statistically significant VE, which was among 

those 18 through 49 years of age at 25% (10, 37). The other estimates were not statistically 

significant for overall VE in the outpatient setting.

The estimates are consistent with the significant antigenic drift or difference in the H3N2 

viruses. These data are different from what was presented in February when some initial 

indication was seen of VE against H3N2 viruses. In the end of season estimate for the 

ambulatory network, A(H1N1)pdm09 VE is 44% (36, 51). This is consistent with the preliminary 

estimates for A(H1N1)pdm09. However, no VE is observed against A(H3N2) with an estimate of 

9% (-4, 20). As noted earlier, a large number of the A(H3N2) viruses were sequenced. Among 

the 773 H3 viruses that were sequenced, there was a VE of 15% (-1, 28). That is similar to the 

overall effectiveness, so CDC believes that there is a good representative sample of the 

A(H3N2) viruses that were sequenced. Importantly, VE against A(H3N2) clade C3.3a viruses 

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(709/773) was 11% (-6, 26). This is very similar to the overall estimate, which would be 

expected. Less than 10% of the samples with the A(H3N2) clade 3C.2a1 that is similar to the 

vaccine virus have been sequenced. However, there is some evidence of VE against the more 

vaccine-like H3 clade of 45% (5, 68). Unfortunately for VE, that was not the predominant clade 

this season.

For HAIVEN, the inpatient adult network, overall VE was 25% (1, 41). There are some 

differences in the point estimates by age group. Patients 18 through 49 years of age had a VE 

of 1% (-58, 38). There is some evidence of VE in patients 50 to 64 years of age with a VE 47% 

(22, 63). There was no significant effectiveness in patient ≥65 years of age with a VE of 15% (-

24, 41). However, the surprising finding in the inpatient network that differs from the finding in 

the ambulatory network is that the estimate against H3N2 is not zero or non-significant as found 

in the ambulatory network but was -43% (-102, -2). The H1N1 estimate is consistent with what 

was seen in ambulatory network at 60% (46, 71). There is evidence of protection in the inpatient 

adult network against H1N1, but no significant protection and a negative point estimate against 

H3N1.

Regarding the NVSN, the pediatric inpatient network for children 6 months to 17 years of age, 

overall VE against any laboratory-confirmed influenza was 31% (5, 51). There is some 

difference in the point estimate by age group, with slightly higher point estimates in patients 9 

through 17 years at 53% (5, 77) than patients 6 months to 8 years of age with 26% (-6, 49). The 

estimates for H3N2 and H1N1 are more consistent with the ambulatory network for children. 

The H3N2 estimate is 13% (-13, 42) and the H1N1 estimate is 48% (14, 68).

It is notable that all three US networks identified no vaccine protection against what 

predominantly was an antigenically different H3N2 3C.3A clade virus this season. There is 

negative VE for H3N2 in the HAVIEN adult inpatient network, which is based on a small number 

of cases and could be related to chance or bias, especially in patients 18 through 49 years of 

age. CDC believes that these findings are unstable in that they are subject to changes with 

small alterations in case or vaccine classification. Because these are preliminary estimates with 

self-reported vaccination status, these estimates will be updated when final vaccination statuses 

become available. One of the comparison groups that has been used for VE studies in the past 

is people who were infected with another virus. In this case, a control group of people infected 

with respiratory syncytial virus (RSV) was utilized. No VE and no negative effectiveness are 

seen if an RSV comparison group is used in the inpatient setting. This suggests that there may 

be some bias in the inpatient setting compared to the outpatient setting. No similar findings of 

increased influenza vaccination rates are seen in the US Flu VE Network or laboratoryconfirmed influenza hospitalization cases in US FluSurvNet compared to HAIVEN. The 

possibility that there is an alternative biological explanation cannot be excluded for negative VE 

in the inpatient setting.

CDC is taking several steps to look further at these estimates and finalize VE estimates for this 

season. As mentioned earlier, they are receiving updated data that will include vaccine 

verification and analysis and there will be further analyses of these VE estimates. In the review 

of preliminary data, especially for the inpatient adult network data, no issues were identified 

related to simple data miscoding or analysis. Additional data extraction is planned, especially for 

underlying conditions to understand the patients who were enrolled in the inpatient adult 

network. In addition to ongoing verification of vaccination status, estimates based on prior 

vaccination history and vaccine type also will be assessed. There is a unique opportunity this 

season to evaluate serologic specimens and virus sequencing for US Flu VE and HAIVEN

network cases. There was an effort with expanded activity in the VE Network to collect acute 

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and convalescent sera from cases and to sequence viruses from the cases. They are hoping 

that this also will provide answers as to these findings for the ambulatory and inpatient network. 

CDC is collaborating with partners in other networks in other countries to compare findings and 

consider possible explanations for these findings. Finally, an update is planned for the ACIP 

Influenza WG in early fall 2019. 

In summary, the overall VE was approximately 30% against influenza illness and 

hospitalizations. CDC is working to try to provide burden estimates as quickly as possible. 

Vaccine likely prevented between about 40,000 to 90,000 hospitalizations based on previous 

seasons’ estimates and data from this season. Vaccine clearly reduced A(H1N1)pdm09-

associated outpatient influenza illness by 44% and hospitalizations by 48% to 60%. However, 

no significant protection was observed against H3N2 illnesses. This is believed to be due to the 

emergence of the antigenically drifted/different A(H3N2) clade 3C.3a. WHO has updated the 

A(H3N2) component of 2019-2020 Northern Hemisphere influenza vaccines to include a virus 

from this 3C.3a clade. As a reminder, these VE estimates are preliminary and will be updated 

when final data are available. 

Discussion Points

Dr. Szilagyi said it was very exciting to see the results from the three networks. He observed 

that there were somewhat similar VEs for the young children in the Flu VE Network and the 

NVSN, but they differed a lot for the children 9 through 17 years of age. Second, while the 

numbers might be small, he pointed out that there also is an opportunity to present results for 

EDs. That is a major source of healthcare and cost. Similarly, it might be possible eventually to 

show data for the number of ED visits and outpatient visits averted.

Dr. Flannery indicated that in the outpatient US Flu VE Network setting, the adjusted VE 

estimate was quite low in children 9 through 17 years of age at 6% (-22, 27) and was quite a bit 

lower than children 6 months through 8 years of age at 49% (38, 58). In NVSN, the estimate for 

children 9 through 17 years of age was 53 (5 to 77). The confidence intervals are wider on the 

estimates from the NVSN, so there are smaller numbers. The two estimates are consistent with 

some protection in the children 6 months through 8 years of age and 9 through 17 years of age

when looking at both networks. However, it was a surprise with the ambulatory network that the 

estimate for children 9 through 17 years of age was not statistically significant and that there 

was not better evidence of protection in that group. CDC is examining further why the 9 through 

17 year group estimates were as low as they were, especially in the ambulatory network. 

Dr. Szilagyi pointed out that this may suggest that it was more protective against severe 

disease.

Dr. Flannery indicated that one of the reasons they set up the comparison between the 

ambulatory and inpatient groups was to examine the question pertaining to whether VE is higher 

against severe disease. In most of the estimates that CDC has presented previously that have 

compared adult networks for ambulatory and inpatient, there has not been a substantial 

difference in VE between the inpatient and outpatient groups. They will further assess this in 

children. There is some logistic difficulty with the two networks in having the correct comparison 

group for the ambulatory sites that do enroll in EDs. While there is some enrollment in EDs, it 

may not be enough to provide an idea of VE for ambulatory patients treated in EDs. In the 

inpatient networks, several of the NVSN sites are enrolling in EDs.

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Dr. Fry (SME) said this is a very good point and later in the summer, they will be able to break 

this apart to examine it further.

Dr. Hunter asked whether there is any way to know what effect the vaccine had on the drifting of 

the strains during the season. That is, without the vaccine, would H1N1 have been more 

predominant and would the strain of H3N2 that was in the vaccine have been more 

predominant? Related to that, he wondered whether there is any theoretical reason that the 

vaccine would have created any pressure for the H3N2 strain that it is not in the vaccine to have 

been more predominant this season.

Dr. Flannery indicated that there is some speculation that with the high vaccination rates in the 

US, that may have contributed to how much of the 3C.3a antigenically different virus was seen 

in the US compared to other countries. There was a lot of interest in how much 3C.3a was 

circulating. The US seemed by far to lead in the percentage of the H3 viruses that were 3C.3a. 

It is not clear whether there was some selection. If the H1N1 virus had predominated the entire 

season or there had been more H1N1, VE may have been higher. However, it was not clear 

whether it would have been a lower H1N1 predominant season with lower vaccine coverage. 

While this is just speculation, CDC is interested in this because of the higher proportion of 3C.3a 

viruses seen in the US than in other countries.

Dr. Messonnier clarified that this is an intellectual exercise and she did not want their listeners to 

perhaps confuse the difference between an intellectually stimulation conversation versus actual 

fact. There are no data to suggest that high vaccination coverage in the US is in any way 

leading to AEs for US citizens.

Dr. Hunter said the other way to think of this was that they just saw the remainder of what is 

going to happen anyway, but it was less H1N1 and less H3N2 of the vaccine strain, and that 

was cut off with high vaccination rates and they were left with what they saw. That is another 

theoretical approach to the “glass half full.”

Dr. Fry (SME) emphasized that this was theoretical.

Dr. Foster (APhA) inquired as to whether there had been any evaluation of the egg-based 

versus cell-based component of the vaccines in terms of effectiveness.

Dr. Flannery indicated that there was a recent study by a DoD group that published 2017-2018 

data from their VE network comparing FluCellVax to an egg-based vaccine that showed a small 

improvement for FluCellVax against the H3N2 viruses that circulated in that season. However, 

CDC will not have the final vaccine type information until later this year from the networks on 

which he just presented. When they do, they will be able to assess whether there is a difference 

between the various vaccine types of egg, recombinant, or cell in the networks.

Dr. Lee said she was still trying to wrap her head around the ins and outs of the test-negative 

design. She wondered how much information they have about chronic conditions or 

comorbidities associated with the patients who are in these populations. It felt to her like there 

was residual confounding and that once that is uncovered, that finding no longer will hold up.

Dr. Flannery replied that the inpatient network is assessing chronic conditions, previous 

hospitalizations, and other differences between the cases and the test-negative comparison 

group. There is a lot more work in the inpatient network than in the ambulatory network to 

assess high risk conditions. However, all three networks include high risk conditions as potential 

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confounders and try to compare high risk conditions among influenza cases and the influenzanegative comparison group.

Thinking about the timing of vaccination of populations with various comorbidities, Dr. Lee 

wondered whether a test-negative design matches by calendar week test-positive and testnegative or if it adjusts for this as a confounder.

Dr. Flannery responded that the design takes into account calendar time in different ways. In the 

ambulatory network, it is 2-week intervals and it is an adjustment as a confounder rather than a 

match design. It is part of the analysis to include calendar weeks.

Dr. Walter added that when the WG was reviewing the data, they were struck by the negative 

value of VE in the HAIVEN network. They were reassured with a different comparison group. 

There is likely some type of bias in the group selection in that particular network.

Dr. Whitley-William (NMA) asked whether there is any information in the vaccinated group 

regarding the timing of when they received influenza vaccination.

Dr. Flannery confirmed that CDC does have that information and will further examine the 

differences in the timing of vaccines among influenza positives and negatives across the 

different networks. 

Dr. Weiser (IHS) noted that a considerable amount of time was spent the previous day talking 

about the indirect effects of pneumococcal vaccine, and he wondered whether Dr. Flannery 

could say anything about the indirect effects of influenza vaccine.

Dr. Flannery replied that they do not measure indirect effects from these networks. They 

measure direct effects of vaccine in these observational data. The work that has been done on 

the indirect effects of vaccine has been done with models.

End-of-Season Update: 2018-2019 Influenza Vaccine Safety Monitoring

Tom Shimabukuro, MD, MPH, MBA

Immunization Safety Office

Centers for Disease Control and Prevention

Dr. Shimabukuro provided a safety monitoring update from VAERS, an RCA from the VSD, and 

an FDA assessment of GBS following influenza vaccine from Medicare data. He also described 

clinical research studies in progress from the Clinical Immunization Safety Assessment (CISA) 

Project. He shared a table defining related terms used in thinking about safety monitoring, which 

also are relevant for pharmacovigilance in general, as well as a table influenza vaccines 

abbreviations: 

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As a reminder, VAERS is a spontaneous reporting system that is co-managed by CDC and 

FDA. As a spontaneous reporting system, its main limitation is that generally causality cannot 

be assessed from VAERS reports alone. VAERS accepts all reports from all reporters without 

making judgments on causality, irrespective of clinical seriousness. As a hypothesis-generating 

system, VAERS identifies potential vaccine safety concerns that can be studied in more robust 

data systems.

This analysis included US influenza vaccine reports from July 2018-April 2019. They performed 

a clinal review of reports, including medical records when available, for all serious reports; 

pregnancy reports for spontaneous abortion (SA), stillbirths, congenital anomalies; and 

anaphylaxis reports in persons with a history of egg allergy. FDA colleagues conducted 

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Empirical Bayesian (EB) data mining to detect disproportional reporting for vaccine-adverse 

event pairings. 

In terms of reports by vaccine type for the 2018-2019 influenza season, probably the most 

notable finding was a relatively small number of doses (n=150) for IIV3. That likely represents 

shifts in the market for product types. The serious and non-serious breakdown is similar to what 

has been observed in previous seasons and is similar across vaccine products. Relatively small 

numbers of reports were GBS, anaphylaxis, and febrile convulsions. There are no data mining 

signals for GBS, anaphylaxis, or febrile convulsion in association with IIV3, IIV4, or IIV3-HD. 

There were no anaphylaxis reports in persons with a history of egg allergy. Febrile convulsion 

reports are limited to children 6 months through 59 months of age. For ccIIV4, aIIV3, RIV4, and

LAIV4, the serious and non-serious breakdown is similar to what has been seen in the past for 

influenza vaccines and these products and is similar across product type. There were no data 

mining signals for GBS, anaphylaxis, or febrile convulsion in association with ccIIV4, aIIV3, 

RIV4, or LAIV4. There was on ccIIV4 anaphylaxis report in a person with a history of egg 

allergy. There were no anaphylaxis reports in persons with a history of egg allergy for aIIV3, 

RIV4, or LAIV. 

There were 141 total reports involving vaccination during pregnancy (IIV4=55, ccIIV4=67, 

IIV3=4, RIV4=6, unknown type/brand=9). The median maternal age at vaccination was 32 

years. Median gestational age at vaccination when reported was 21 weeks. The breakdown of 

trimester in those reports was pretty evenly split at 36 (31%) in the first trimester, 44 (38%) in 

the second trimester, and 37 (32%) in the third trimester. In 44 (31%) of these reports, there 

was a pregnancy-specific AE. These included: spontaneous abortion (13), preterm delivery (9), 

premature labor (6), stillbirth (2), pre-eclampsia (2), oligohydramnios (2), placenta previa (2), 

dysmature placenta (2), premature rupture of membranes (1), gestational hypertension (1), 

gestational diabetes (1), placentae abruption (1), vaginal discharge (1), and nausea (1). In 18 

(13%) reports, there was an infant or fetal AE. These included: low birth weight (5), large for 

gestational age (2), meconium in amniotic fluid (2), nuchal chord (1), hypospadias and 

chyothorax (1), dystocia of shoulder (1), intrauterine growth retardation (1), jaundice (1), 

tricuspid regurgitation and pulmonary insufficiency (1), upper respiratory tract infection, (1), 

cystic fibrosis carrier (1), and asymmetrical growth (1). 

To summarize VAERS monitoring, no new safety concerns were detected for IIV3, IIV4, LAIV4, 

IIV3-HD, ccIIV4, aIIV3, or RIV4 during the 2018-2019 influenza season. Surveillance for the 

2019-2020 influenza season will include enhanced safety monitoring for aIIV3 (FLUAD®), RIV4 

(Flublok® Quadrivalent), pregnancy reports, and anaphylaxis reports in persons with a history of 

egg allergy. 

Regarding the RCA in the VSD, there are 8 participating integrated healthcare organizations in 

the VSD collaborating with CDC: Kaiser Permanente Washington, Kaiser Permanente 

Northwest, Kaiser Permanente Northern California, Kaiser Permanente Southern California, 

Kaiser Permanent Colorado, HealthPartners, Marshfield Clinic Research Institute, and Harvard 

Pilgrim. The VSD has medical care and demographic data on over 12.1 million persons per year 

(~3.7% of U.S. population). It links vaccination data to health outcome data and is used for 

surveillance and research. The VSD includes data on immunizations, outpatient and clinic visits, 

ED visits, hospital discharge codes, procedure codes, birth and death certification information 

and family linkage, and enrollment and demographic information. CDC has access to EHRs and 

paper charts.

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For influenza RCA in the VSD, CDC uses two methods: the self-controlled risk interval (SCRI) 

method and the current versus historical methods. In the SCRI, patients serve as their own 

controls and events in the risk window are compared to events in the comparison window. Risk 

and comparison windows vary by the actual outcome. In the current versus historical method, 

events in the risk window in the current season compared to events in the risk window in the 

historical period. For influenza vaccine, CDC performs weekly near real-time sequential 

monitoring to detect statistical signals for pre-specified outcomes. They focused on standard 

dose IIV4 and IIV3 High-Dose. Use of other influenza vaccine products was still relatively low in 

VSD. Just a small amount of IIV3 vaccine was used in the VSD.

In terms of background, RCA in the VSD is a powerful and sophisticated tool for near real-time 

vaccine-safety monitoring using sequential monitoring techniques. It employs an automated 

analysis that uses ICD-coded diagnoses from administrative data. It is a surveillance activity for 

signal detection and signal refinement, which is not the same as an epidemiologic study for 

signal evaluation and causality assessment. It is designed to detect statistical signals, which are 

values above specified statistical thresholds. When a statistical signal occurs, CDC conducts a 

series of evaluations using traditional epidemiologic methods. Chart-confirmation of diagnoses 

to confirm or exclude cases as true incident cases is a key part of statistical signal assessment. 

Importantly, not all statistical signals represent a true increase in risk for an AE.

RCA outcomes for the 2018-2019 influenza season include acute disseminated 

encephalomyelitis (ADEM), anaphylaxis, Bell’s Palsy, encephalitis, GBS, seizures, and 

transverse myelitis. A total of 5.4 million dose 1 influenza vaccines were administered as of April 

3, 2019 in VSD. Just over 70% of these were standard dose IIV4, 12% were IIV3 High-Dose, 

9% were ccIIV4, 0.5% were aIIV3, and 7% were RIV4. This is a summary table of statistical 

signals detected during monitoring for the past influenza season:

The table includes only the vaccines for which there was a statistical signal, the date, and the 

analysis. Dr. Shimabukuro reviewed each of these in more detail starting with anaphylaxis.

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A statistical signal was detected the week of October 21, 2018 for anaphylaxis following IIV4 in

the current versus historical analysis. The risk interval was 0 to 2 days and the age group was 

individuals ≥6 months. There were 9 observed events compared to 3.1 expected events, which 

is a RR of 2.88. That generated a log likelihood ration (LLR) at that time of 3.66, which exceeds 

the critical value of 3.0. Mathematically, this detected a statistical signal. For the end-of-season 

analysis, CDC chart reviewed 18 potential cases as 9 additional cases came in during the 

seasons. Of those, 11 had symptom onset prior to vaccination (i.e., other exposures and 

vaccinated in ED), 6 had onset post-vaccination but with other exposures to explain anaphylaxis

like foods (3), medications (2), or exercise-induced (1); 1 case was determined to be potentially 

vaccine related in which the patient received IIV4 and recombinant zoster vaccine 

simultaneously. After chart review, there was an observed rate of 0.26 cases/1 million 

vaccinated, which is below the published VSD rate of 1.6 cases/1 million vaccinated. 

A statistical signal was detected the week of November 11, 2018 for anaphylaxis following 

ccIIV4 in the current versus historical analysis. The risk interval was 0 to 2 days and the age 

group was individuals ≥4 years. There were 4 observed cases and 0.5 expected cases for a RR 

of 7.61. For the end-of-season analysis, CDC chart reviewed 7 potential cases, which included 

3 additional cases that came in. After adjudication of these 7 cases, 0 cases were determined to 

be related to vaccine. Most had symptoms prior to vaccination and other exposures included 

codeine, naproxen, milk, and gentamicin. 

There was a statistical signal the week of December 9, 2018 for Bell’s Palsy following ccIIV4 in

the self-controlled risk interval analysis. The risk interval was 1 to 42 days, the age group was 4 

through 7 years of age. There were 4 events in the risk window and 1 in the comparison window 

for a RR of 4, which reached the threshold for a statistical signal. When the chart review was 

done, 1 of the 4 cases in the risk window had an initial diagnosis of Bell’s Palsy. However, it was 

later determined that symptoms were related to acute otitis media on day 4 after vaccination. 

The other 3 cases were determined to be Bell’s Palsy with symptom onset in the risk window. 

The case in the comparison window was determined to be Bell’s Palsy with symptom onset 55 

days prior to vaccination. For the final chart reviewed SCRI signal assessment, there were 3 

cases in the risk window and 1 case in the comparison window for a RR of 3.0 (95% CI: 0.31-

28.8). While there is an elevated risk, the confidence interval is very wide. In the current versus 

historical analysis for Bell’s Palsy using automated data a statistical signal was not detected.

A statistical signal was detected the week of November 25, 2018 for seizures following IIV4 in

the SCRI analysis. The risk interval was 0 to 1 day and the age group was 6 months to 23 

months. There were 10 events in the risk window and 11 in the comparison window, which 

generated a RR of 3.18. The LLR exceeded the critical value and there was a statistical signal. 

There also were statistical signals for seizures following IIV4 among children 24 through 59 

months of age. In the SCRI analysis, the signal occurred the week of November 4, 2018. The 

signal occurred the week of December 9, 2019 in the current versus historical analysis. In terms 

of the final SCRI analysis using chart confirmed cases of febrile seizures. The VSD RCA looks 

at the outcome of seizure. The records are assessed to confirm that these are incident febrile 

seizure cases. In the 6-23 months age group, there was an elevated IRR of 2.41 (1.12-5.18)

and an attributable risk of 4.24/100,000 doses administered. For the 24-59 month age group, 

there was an elevated IRR of 3.50 (1.01-12.09) and an attributable risk of 1.80/100,000 doses 

administered. Looking at the age group in total by vaccine, there were elevated IRR for IIV4 

alone, IIV4 administered with any other vaccine, and IIV administered with PCV13. These 

ranged from 2.33 to 2.92 and not all reached statistical significance. The attributable risks were 

1.6/100,000 for IIV4 alone, 4.84/100,000 for IIV4 with any other vaccine, and 4.73/100,000 for 

IIV4 with PCV13.

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A statistical signal was detected the week of December 9, 2018 for GBS following IIV3 highdose in the SCRI analysis. The risk interval was 1 to 42 days and the age group was ≥65 years. 

There were 5 events in the risk window and no events in the comparison window for a RR of 11, 

which signaled. In the last SCRI analysis on April 3, 2019, there were 8 events in the risk 

window and 1 event in the comparison window for a RR of 8. The statistics were not generated 

for this because once there is a signal, there always is a signal, so there is no point in 

generating the LLRs. Upon chart reviews and adjudication of the 8 cases in the risk window, 1 

GBS case was classified as Brighton Collaboration Level 2. The other 7 GBS cases were ruled 

out as prevalent/non-incident cases, had alternate diagnoses, had symptom onset prior to or on 

day of vaccination, and/or lacked clinical evidence to confirm that it was GBS. The 1 GBS case

in the comparison window was classified as Brighton Collaboration Level 1. After case 

adjudication there was 1 case in the risk window and 1 case in the comparison window for a RR 

of 1.0. No statistical signal had been observed by April 3, 2019 for the corresponding current 

versus historical analysis. 

The FDA, CDC, CMS conducted an SCRI analysis of GBS following influenza vaccine to further 

assess this within the CMS database, which contains substantially more data on individuals 65 

years of age and older. The SCRI used an 8-21 day risk interval for the association between 

influenza vaccines and GBS. The data source was Medicare claims data for ≥65 years of age. It 

included more than 12 million beneficiaries in total, more than 7 million of whom received IIV3-

HD. An end-of-season analysis is planned. For the results, the highest point estimate was for 

IIV3-HD. There were 16 cases in the 8-21 day risk interval and 26 cases in 43-84 day control 

interval for an odds ratio of 1.85 (95% CI 0.99, 3.44; p-value = 0.054) and attributable risk of

0.98/1 million vaccinations. The magnitude of the odds ratio is similar to what has been 

observed in previous seasons and the attributable risk is consistent with the labeled risk of GBS. 

In summary of VSD RCA monitoring for influenza vaccine 2018-20191, following signal 

assessment and end-of-season analysis the statistical signals for anaphylaxis following IIV4 and 

ccIIV4 were ruled out. The finding of an elevated risk for Bell’s Palsy following ccIIV4 in 4 to 17 

year olds was based on a small number of cases and doses. There was an elevated RR of 3.0 

but the confidence interval was very wide and included 1.0. CDC will continue to monitor and 

explore options for additional analyses. The 2001-20062 case-centered analysis with IIV3 did 

not find an association between Bell’s Palsy and influenza vaccine. The statistical signal for 

GBS following IIV3-HD among individuals ≥65 years of age was ruled out. The preliminary FDA 

analysis of GBS following IIV3-HD in CMS data indicated that the risk, if any, is no greater than 

in some previous seasons and consistent with labeled risk of GBS [1Including FDA analysis of 

GBS and IIV3-HD; 2Rowhani-Rahbar et al. Immunization and Bell's palsy in children: a casecentered analysis. Am J Epidemiol. 2012;175(9):878-85]. 

The final SCRI analysis of confirmed febrile seizure cases showed an elevated IRR in children 

aged 6-23 and 24-59 months. The risk was similar in those who received IIV4 alone and those 

who received IIV4 simultaneously with other vaccines, including PCV13. In some previous 

seasons, risk was greater with simultaneous PCV13. Attributable risk was less than that 

observed in some previous influenza seasons and less than the febrile seizure risk associated 

with MMR or PCV. This finding for febrile seizures in children in these age groups is not new. It 

has been observed in some previous seasons since it was first detected in 2010-2011. The 

magnitude of this risk does not exceed what has been observed some previous seasons.

In closing, Dr. Shimabukuro provided this table that lists some of the CISA clinical influenza 

vaccine studies that are in progress, which are all posted on clinicaltrials.gov:

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Discussion Points

Dr. Atmar questioned the control period for some of the neurologic outcomes -56 to -15. It 

seemed to him that there might be some bias about under-use of vaccine if a patient has a new 

diagnosis in that time interval. He wondered why that was selected or whether there is any 

evidence that new diagnosis in that timeframe might affect subsequent vaccination.

Dr. Shimabukuro replied that choosing comparison windows has been challenging. There have 

been discussions about using a pre-exposure comparison window and the bias that might be 

introduced for people who have that event who may be less likely to get vaccination. This 

certainly can be reevaluated.

Dr. Plescia (ASTHO) emphasized the importance of the safety and efficacy data, but pointed out 

that they are fairly difficult for the public to understand. The ASTHO membership struggles with 

this a great deal. While CDC and other vaccine groups do a nice job of communicating this on 

their websites, he wondered whether CDC could provide updates on ways they are thinking 

about communicating these data.

Dr. Messonnier indicated that they are in active discussions with ASTHO about this, and they 

are open to suggestions. This is an issue with which everyone struggles. Understanding these 

data requires a systematic approach to work through the data, and it is difficult to figure out how 

to communicate that effectively to the public.

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Influenza Work Group Considerations and 

Proposed 2019-2020 Season Recommendations

Lisa Grohskopf, MD, MPH

Influenza Division, CDC

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Grohskopf began by thanking the CDC personnel who participate in and contribute to this 

WG discussions on an ongoing basis each year. She thanked Dr. Walter for his amazing 

leadership of the WG for the last 3 years, and welcomed Dr. Atmar as the new Chair.

During this session, Dr. Grohskopf reviewed the WG considerations and the proposed 

recommendations for the 2019-2020 seasons recommendations. Some of this material was 

discussed either earlier in the day or in previous meetings over the past year or less. No 

substantial changes were proposed for the coming season. The core recommendation remains 

unchanged, which is that:

Annual influenza vaccination is recommended for all persons aged 6 months and older 

who do not have contraindications. 

There are two primary updates to the vaccine compositions, the first of which is the vaccine 

composition. In most seasons, there is a change in the vaccine composition. For the 2019-2020 

composition, there are changes in the influenza A(H1N1) and A(H3N2) components for the 

following compositions for trivalent and quadrivalent vaccines:

Trivalent Vaccines

 A/Brisbane/02/2018 (H1N1)pdm09-like virus—updated

 A/Kansas/14/2017 (H3N2)-like virus—updated

 B/Colorado/06/2017-like virus (Victoria lineage) 

Quadrivalent Vaccines

 A/Brisbane/02/2018 (H1N1)pdm09-like virus—updated

 A/Kansas/14/2017 (H3N2)-like virus—updated

 B/Colorado/06/2017-like virus (Victoria lineage)

 B/Phuket/3073/2013-like virus (Yamagata lineage)

As Ms. Brammer mentioned earlier, this year was somewhat unusual in that there was a delay 

in the selection H3N2 component of the vaccine. Typically, WHO meets during the last week of 

February to make recommendations for all components for the following Northern Hemisphere 

season. This year, selection of the H3N2 component was delayed by approximately a month.

With that delay, one question that arises pertains to whether there may be a delay in the 

availability of vaccine. The following table was compiled by Dr. Jeannie Santoli in CDC’s ISD to 

summarize projected supply in terms of number of doses for this seasons, as well as projected 

timelines as far as CDC has been made aware of them to date:

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Maximum Projected Supply: 162-169 Million Doses*

Manufacturer Distribution Estimated to Begin

AstraZeneca Early September

GSK Mid-August

Sanofi Pasteur Late August/Early September

Seqirus Mid-August

*Information presented 5/16/19 at the National Adult Immunization and Influenza Summit, confirmed June 2019. The 

estimate aggregates information across manufacturers about potential maximum production for the season and could 

change based on production yield, lot release, and demand for vaccine. 

The second set up updates relates to licensure changes that occurred since the publication of 

the 2018-2019 Statement. These were discussed during both the October 2018 and February 

2019 meetings. There have been two licensure changes involving Afluria® Quadrivalent and 

Fluzone® Quadrivalent. The result of these changes is that for the youngest group of vaccinees, 

children 6 months through 35 months, it is anticipated that there will be 4 licensed IIVs for which 

the indicated dose volumes differ as follows: 

 Fluarix® Quadrivalent (IIV4, GSK) 0.5 mL 

 FluLaval® Quadrivalent (IIV4, ID Biomedical Corp/GSK) 0.5 mL

 Fluzone® Quadrivalent (IIV4, Sanofi Pasteur)* 0.25 mL or 0.5 mL

 Afluria® Quadrivalent (IIV4, Seqirus)* 0.25 mL

One of the observations discussed in the WG conversations is that this is a potential source of 

confusion for HCP. To that end, a very small third table has been added to the Influenza 

Statement that summarizes the dose volumes in this age group. Of note, for individuals over 36 

months of age or ≥3 years, the dose volume is the same at 0.5 mL.

In addition, there are a few areas of minor edits to the 2019-2020 guidance language that were 

highlighted in the copy of the Draft Statement that was circulated to ACIP members including 

the following:

Timing of Vaccination 

The language concerning July/August vaccination was moved to the top paragraph: 

“For those requiring only one dose for the season, early vaccination (i.e., in July and August) 

is likely to be associated with suboptimal immunity before the end of the influenza season, 

particularly among older adults.” 

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Groups That Should be the Focus of Efforts if Supply is Limited 

The language describing HCP has been made consistent with “2011 ACIP Recommendations 

for the Immunization of Health Care Personnel.”

Vaccine Doses Needed for Children Aged 6 Months Through 8 Years

The language was clarified to indicate that 8-year-olds needing two doses should receive the 

second dose even if they turn 9 years of age between dose 1 and dose 2, which is consistent 

with AAP guidance. 

Concomitant Receipt of Two Vaccines Containing Novel Adjuvants

This section notes that given limited safety data, non-adjuvanted influenza vaccines may be 

considered when giving another vaccine containing a novel adjuvant, and that vaccination 

should not be delayed if a specific product is not available. 

Dr. Grohskopf concluded that the proposed vote would be as follows:

ACIP affirms the updated statement “Prevention and Control of Seasonal Influenza with 

Vaccines: Recommendations of the Advisory Committee on Immunization Practices—

United States, 2019-20 Influenza Season.”

Discussion Points

An inquiry was posed regarding whether the information about receipt of two vaccines 

containing novel adjuvants would be reflected on the Vaccine Information Statement (VIS) as 

well.

Dr. Grohskopf said that while the WG did not discuss this, they could look into having it reflected 

on the VIS as well.

Dr. Messonnier added that CDC is happy to discuss the VIS separately, which involves a fairly 

complicated process between CDC and FDA that includes a public comment process to decide 

what is on the form. They have been struggling with how to make that sheet the most effective 

way to communicate appropriately to the public, because it has come to their attention that it is 

not always interpreted like it is intended. Therefore, this is perhaps part of a broader 

conversation about the best use of the VIS.

Dr. Walter made a motion to approve the recommendation as presented. Dr. Ault seconded the 

motion.

The motion was stayed until the voting session later in the day; however, the vote is included 

with this session for continuity.

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Motion/Vote: Influenza Vaccines 

Dr. Walter made a motion to affirm the updated statement “Prevention and Control of Seasonal 

Influenza with Vaccines: Recommendations of the Advisory Committee on Immunization 

Practices—United States, 2019-20 Influenza Season.” Dr. Ault seconded the motion. No COIs 

were declared. The motion carried with 14 affirmative votes, 0 negative votes, and 0 

abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Updates: Influenza Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch indicated that the purpose of this resolution was to update the table of inactivated 

influenza vaccines in the VFC program. Yellow highlighting was used to indicate changes to the 

resolution in comparison to the prior approved version. There is no change to the eligible 

groups, which are all children aged 6 months through 18 years. The recommended vaccination 

schedule also remains unchanged in that children 6 months through 8 years of age should 

receive 1 or 2 doses as noted in the current ACIP recommendations and children 9 through 18 

years of age should receive 1 dose. 

The updated table below lists the currently approved inactivated influenza vaccines in the VFC 

program, including the age indications for each vaccine: 

Brand Name Presentation Age Indication

Afluria (Quadrivalent) 0.25mL pre-filled syringe 6 through 35 months

Afluria (Quadrivalent) 0.5 mL pre-filled syringe >= 36 months

Afluria (Quadrivalent) 5.0mL multi-dose vial >=6 months

Fluarix (Quadrivalent) 0.5 mL pre-filled syringe >= 6 months

Flucelvax (Quadrivalent) 0.5 mL pre-filled syringe >= 4 years

Flucelvax (Quadrivalent) 5.0mL multi-dose vial >= 4 years

Flulaval (Quadrivalent) 0.5 mL pre-filled syringe >= 6 months

Flulaval (Quadrivalent) 5.0 mL multi-dose vial >= 6 months

Fluzone (Quadrivalent) 0.25mL pre-filled syringe >= 6 through 35 months

Fluzone (Quadrivalent) 0.5mL prefilled syringe/single-dose vial >= 6 months

Fluzone (Quadrivalent) 5.0mL multi-dose vial >= 6 months

Note: The use of brand names is not meant to preclude the use of other comparable licensed vaccines. 

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Recommended Intervals/Doses, Contraindications and Precautions, and the Statement 

Regarding Update Based on Published Documents remain unchanged for inactivated and live 

attenuated influenza vaccine.

Motion/Vote: VFC Resolution for Influenza Vaccines 

Dr. Walter made a motion to approve the VFC resolution for influenza vaccines. Dr. Frey

seconded the motion. No COIs were declared. The motion carried with 14 affirmative votes, 0 

negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Introduction

Kelly L. Moore, MD, MPH

Chair, Hepatitis Vaccines WG

Vanderbilt University School of Medicine

Dr. Moore indicated that the term of reference for the Hepatitis WG with respect to hepatitis A 

(HepA) focused on updating the HepA vaccine recommendations that were published originally 

in 2006. Since that time, three other sets of specific recommendations were published on HepA, 

including the following:

 “Updated Recommendations from the ACIP for Use of Hepatitis A Vaccine in Close 

Contacts of Newly Arriving International Adoptees,” MMWR, September 18, 2009, Vol 58, 

#36 

 “Updated Recommendations from the ACIP for Use of Hepatitis A Vaccine for Postexposure 

Prophylaxis and for Preexposure Prophylaxis for International Travel,” MMWR, November 2, 

2018, Vol 67, #43 

 “Recommendations of the Advisory Committee on Immunization Practices for Use of 

Hepatitis A Vaccine for Persons Experiencing Homelessness,” MMWR, February 15, 2019, 

Vol 68, #6 

In the period of time between May 2014 and June 2019, the WG has had 31 meetings focused 

on HepA topics. Between March 2019 and June 2019, they have had 5 meetings related to the 

proposed update of the HepA vaccine statement.

Hepatitis Vaccines

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Dr. Moore indicated that during this ACIP meeting, members would hear presentations 

pertaining to 3 topics upon which they would vote. The first topic would be a vote on HepA 

routine catch-up vaccination of children through the age of 18 years, transitioning from the 

current wording that is more optional as a consideration for catch-up from the 2006 

recommendations. In terms of background, HepA vaccines have demonstrated safety and 

efficacy for over 20 years. Nearly the entire cohort of children aged 13-17 years assessed in 

2017, living in states where vaccination was recommended in 2006, were not yet subject to the 

routine recommendation for childhood vaccination. Yet as of 2017, more than 3 out of 4 teens 

had initiated the series and over 2/3 were fully vaccinated. A large majority of states (40%) had 

a daycare or school mandate, or both, for HepA vaccination in 2018, increasing over time from 

HepA vaccine introduction. This suggests that there is widespread acceptance and embracing 

of this vaccine despite the optional recommendation for catch-up in that population. Of the 30 

state immunization information systems (IIS), 27 already routinely forecast HepA vaccine as 

being due for an 18 year old who has never been vaccinated according to the American 

Immunization Registry Association (AIRA). This demonstrates that for the vast majority of IISs, 

no changes would be necessary in order to embrace a routine catch-up recommendation.

The second topic on which there would be a vote would be on HIV as a risk group for increased 

HAV infection severity. As a reminder, when persons with HIV (PWHIV) are co-infected with 

HepA virus (HAV) infection, they experience higher peak HAV viral loads and a prolonged 

duration of HepA viremia than persons without HIV infection. The good news is that PWHIV 

usually do respond to HepA vaccination, particularly when the CD4 cell count is >200 cells/mm3 

and the PWHIV has a low HIV RNA viral load. HIV co-infection outbreak data are available for a 

limited number of outbreak associated states, indicating excess risk of PWHIV to HAV infection 

in those states. Data from the Medical Monitoring Project (MMP) also indicate substantial HAV 

infection among PWHIV. 

The third topic on which there would be a vote would be the full updated HepA vaccine 

statement. This includes a number of modifications, including removal of a risk group for whom 

the WG could no longer identify any excess risk; that is, persons with clotting-factor disorders.

The next step for the Hepatitis WG is to continue its deliberations by moving on to adult HepB 

vaccination topics. 

Hepatitis A Vaccines

Noele Nelson, MD, PhD, MPH

CDC Lead, ACIP Hepatitis Vaccines WG

National Center for HIV/AIDS, Viral Hepatitis, STD, and TB Prevention

Centers for Disease Control and Prevention

Dr. Nelson’s presentation included an overview of HAV epidemiology and Hep A vaccines; a 

presentation of the EtR Framework for catch-up HepA vaccination; a review of the EtR 

Framework that was presented during the February 2019 ACIP meeting for persons with HIV as 

a recommended risk group for HepA vaccination; updates for pregnancy and clotting-factor

disorders; and presentation of the proposed HepA recommendations and updates deliberated 

on by the WG. 

Data collection for HepA started in 1966. The highest number of HepA cases reported was in 

1971 when approximately 60,000 cases were reported at a rate of 30 cases/100,000 population.

Vaccine was recommended in 1996. From 1996-2011, there was a 95.5% decrease in reported 

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cases. The number of reported cases fluctuated slightly from 2011-2015 due to outbreaks, but 

has started to increase sharply since then. In 2017, there were 3365 reported cases [CDC, 

National Notifiable Diseases Surveillance System (NNDSS); Armstrong GL. Pediatrics

2007;119:e22-9].

The rate of reported cases was 1.0 case/100,000 population in 2017 nationally, the highest rate 

since 2007. Looking at the rates of reported cases by age group, in 2017, persons aged 30-39 

years had the highest rate at 2.07 cases/100,000 population, followed by persons aged 40-49 

years at 1.53 cases/100,000 population and persons aged 20-29 years at 1.45 cases/100,000 

population [CDC, National Notifiable Diseases Surveillance System; Pre-Decisional; for federal 

use only; not for distribution].

Widespread outbreaks of HepA have occurred across the US since 2016. Since the outbreaks 

were first identified, 24 states have publicly reported the following as of June 21, 2019: 20,512 

cases; 11,776 hospitalizations (57% of cases); and 194 deaths. The number of deaths due to 

HAV infection had been very low historically, though disease severity is known to increase with 

age. The high number of deaths in the current outbreaks is likely due to co-morbidities and 

underlying health conditions of the HepA cases, something that requires further investigation

[https://www.cdc.gov/hepatitis/outbreaks/2017March-HepatitisA.htm].

Data from the National Notifiable Diseases Surveillance (NNDSS) system show that HepA 

incidence rates have increased dramatically in the wake of the outbreaks. In 2015, during a nonoutbreak year, the national HepA incidence rate was 0.4 cases/100,000 population. Based on 

preliminary data, the national HepA incidence rate increased to 3.8 cases/100,000 population 

during 2018. The increased incidence rates are even more dramatic when compared at the 

state level. In 2018, state HepA incidence rates ranged between 0 cases/100,000 population in 

Alabama, Montana, and North Dakota to 111.92 cases/100,000 population in West Virginia

[National Notifiable Diseases Surveillance (NNDSS), US Census Bureau; 2018 data are 

preliminary].

This latest National Epi curve also was created with NNDSS data. Due to reporting lag and the

relatively long incubation period of the virus, the far right side of the curve is subject to change: 

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To summarize the changing epidemiology, asymptomatic children were associated with HAV 

transmission in past outbreaks in the pre-vaccine era. Now, recent outbreaks are occurring 

primarily among adults. Among states with publicly available case information by age group, the 

median age of HepA cases is in the 30-39 year age range, with a substantial percentage of 

cases aged in the 20-29 and 40-49 year age range. In the current outbreaks, disease severity is 

thought to be due to comorbidities and the poor underlying health of many HAV associated 

cases, including persons co-infected with HepB and HepC. Many cases have occurred among 

persons who use drugs and persons experiencing homelessness. Person-to-person contact, 

crowding, and poor hygiene are thought to contribute to virus transmission among these groups. 

Increases of HAV infections also have occurred among MSM. These outbreaks are estimated to 

cost tens of millions of dollars in healthcare expenditures. Though person-to-person spread is 

now the predominant mode of HepA virus transmission, sporadic foodborne outbreaks also 

continue to occur.

Two inactivated single-antigen HepA vaccines are licensed in the US. HAVRIX® was licensed in 

1995 and VAQTA® in 1996. A combined HepA/HepB vaccine, TWINRIX®, also is available in the 

US for adults aged ≥18 years. In a clinical trial, VAQTA®’s efficacy in protecting against clinical 

HepA was 100% among over 1000 New York children aged 2 to 16 years who received one

dose while living in a community with a high HepA disease rate1. HAVRIX®’s efficacy in 

protecting against clinical HepA was 94% among more than 38,000 Thai children aged 1 

through 16 years who received two doses 1 month apart while living in villages with high HAV

disease rates2. After 3 doses of TWINRIX®, antibody responses are equivalent to responses 

seen after the single antigen vaccines administered separately on standard schedules [1

Werzberger, A et al. New Engl J Medicine. 1992;327:453–7; 2Innis BL, et al. JAMA 

1994;271:1328–34].

All licensed vaccines are highly immunogenic when administered to children and adolescents. 

Of persons aged 2-18 years, 97% to 100% had protective levels of antibody 1 month after 

receiving the first dose and 100% had protective levels 1 month after the second dose, with high 

GMTs. All licensed vaccines are highly immunogenic in persons aged >18 years when 

administered according to the recommended schedules. Protective antibody levels were 

identified in 94% to 100% of immunocompetent adults 1 month after the first dose. After the 

second dose, all persons had protective levels of antibody with high GMTs [1Clemens R et al. J 

Infect Dis 1995;171(Suppl 1):S44–9; 2Nalin DR. VAQTATM, Drugs of the Future 1995;20:24–9; 

3McMahon BJ, et al. J Infect Dis 1995;171:676–9; 4Sharapov et al. Hepatology, 2012; 56: 516–

522; 5Van Herck et al. Expert Review of Vaccines 2005; 4(4): 459-471]. 

Anti-HAV has been shown to persist in vaccine recipients for at least 22 years in adults 

administered inactivated vaccine as children with a 3-dose schedule, which has been shown to 

be equivalent to the current 2-dose schedule. At least 20 year anti-HAV persistence was 

demonstrated among adults vaccinated with a 2-dose schedule as adults. Detectable antibodies 

are estimated to persist for 40 years or longer based on mathematical modeling and anti-HAV 

kinetic studies. Protection following natural infection is lifelong and may also be following 

vaccination [1Mosites, E, et al. J Med Virol. 2018; 90: 1418–1422.; 2Theeten H, et al. Vaccine. 

2015 Oct 13;33(42):5723-7; 3Hens N, et al. Vaccine. 2014;32(13):1507-1513]. 

In pre-licensure trials, adverse reactions to HAVRIX®, VAQTA®, and TWINRIX® were mostly 

injection site reactions and mild systemic reactions. Post-marketing surveillance for AEs 

following receipt of HepA vaccines has been performed primarily by VAERS and VSD. No 

unusual or unexpected safety patterns were observed for any of the HepA vaccines licensed in 

the US. Additional detailed safety data was presented in GRADE presentations at the February 

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2018, October 2018, and February 2019 ACIP meetings, with additional information on vaccine 

safety in pregnancy to be shown later in this presentation [Vaccine Information Statement (VIS) 

https://www.cdc.gov/vaccines/hcp/vis/vis-statements/hep-a.html; MMWR 2006;55(RR-7); 

Unpublished CDC].

HepA vaccination was introduced incrementally in the US from 1996-1999. In 1996, vaccine 

was recommended for children at age 2 years in communities with high rates of disease and 

children at age 2 years and older children in outbreaks. In 1999, vaccine was recommended for 

children at age 2 years in 11 states (Washington, Oregon, Idaho, California, Nevada, Utah, 

Arizona, New Mexico, Oklahoma, South Dakota, Alaska) with average annual HepA rates of 2

times the national average or ≥20 cases/100,000 population. Vaccine was considered in 6 

states (Montana, Wyoming, Colorado, Texas, Missouri, and Arkansas) with rates above the 

national average or ≥10 cases/100,000 population. Routine vaccination was recommended in 

2006. Universal early childhood vaccination was recommended for use at age 12-23 months in 

all states. Existing vaccination programs for children ages 2-18 years were recommended to 

continue. Catch-up vaccination in outbreaks and areas with increasing disease rates could be 

considered. Any person wishing to obtain immunity is recommended for HepA vaccine [MMWR 

1996;45(RR-15); MMWR 1999;48(RR-12); MMWR 2006;55(RR-7)].

In addition, groups at increased risk of HAV infection or severe HAV disease are recommended 

to receive HepA vaccine. These groups include:

 Travelers

 Men who have sex with men

 Users of injection and non-injection drugs

 Persons with clotting-factor disorders [proposed for removal] 

 Persons with occupational risk for infection

 Persons who anticipate close personal contact with an international adoptee

 Persons experiencing homelessness 

 Persons with chronic liver disease 

 Persons with HIV [proposed for addition]

Dr. Nelson noted that during this session, the WG deliberations regarding adding persons with 

HIV as an indication for vaccination would be discussed.

In terms of HepA vaccine coverage in 2017, 1for children aged 19-35 months, ≥2 dose coverage 

was 59.7% and ≥1 dose coverage was 86.0%. The ≥2 dose coverage is likely underestimated 

since the first dose can be given up to age 23 months, with the second dose administered at 

least 6 months after the first. 2For adolescents age 13-17 years, ≥2 dose coverage was 68.4% 

and 1 dose coverage was 77.2%. 3For adults ≥19 years, ≥2 dose coverage was 10.9%; 17.7% 

for travelers and 20.8% for persons with chronic liver disease (CLD). These rates are slightly 

higher when considering adults in the limited range of 19 through 49 years [1Hill HA, et al. 

MMWR 2018;66:1171–1177; 2Unpublished data from Assessment Branch/ISD/NCIRD/CDC – 

Not for Distribution; 3Vaccination Coverage Among Adults in the United States, National Health 

Interview Survey, 2017; https://www.cdc.gov/vaccines/imz-managers/coverage/adultvaxview/ 

pubs-resources/NHIS-2017.html#box2]. 

Regarding estimated HepA vaccine coverage in 2017 in relation to other selected vaccines 

among adolescents aged 13-17 years, Tdap ≥1 dose coverage was 88.7%. Coverage with ≥1 

dose of quadrivalent meningococcal conjugate vaccine was 85.1%. Coverage for ≥1 and ≥2 

HepA vaccine coverage follows at 77.2% and 68.4%, respectively. Coverage with ≥1 dose of 

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HPV vaccine, which was introduced in 2011, was 65.5%. Coverage with ≥2 doses of 

quadrivalent meningococcal conjugate vaccine and ≥3 doses HPV coverage are lower. Thus, 

coverage for HepA vaccine among adolescents aged 13-17 years is comparable to other 

vaccines administered to adolescents for which a routine catch-up vaccination recommendation 

exists [Estimated Vaccination Coverage with Selected Vaccines and Doses* among 

Adolescents Aged 13-17 Years, by Survey Year — National Immunization Survey-Teen, United 

States, 2008-2017; Includes unpublished data from Assessment Branch/ISD/NCIRD/CDC–Not 

for Distribution].

As of October 2018, approximately 44% of states have introduced mandates for daycare or 

daycare plus school or school alone compared to 28% of states in 2011. The increase in 

mandates is likely partially responsible for the increase in adolescent HepA vaccine coverage

[Immunization Action Coalition: http://www.immunize.org/pdfs/hepa.pdf].

Currently, ACIP recommends HepA vaccination for all children aged 12-23 months, with a 

shared clinical decision-making recommendation for catch-up vaccination. The WG proposes 

strengthening this recommendation to include routine catch-up. The proposed recommendation 

is as follows, “ACIP recommends that all children and adolescents aged 2 through 18 years who 

have not previously received HepA vaccine be vaccinated at any age (i.e., children and 

adolescents are recommended for catch-up vaccination).” This language aligns with the HepB 

vaccine statement language.

The policy question and PICO for catch-up vaccination are as follows, “Should HepA catch-up 

vaccination be recommended for children aged 2-18 years?” The population is children aged 2-

18 years and the intervention is HepA vaccination (HepA vaccine series). The comparison is 

HepA vaccination based on shared clinical-decision making, and the outcomes of interest

include HepA infection and AEs. With that in mind, Dr. Nelson presented the EtR Framework for 

catch-up vaccination.

In terms of Criterion 1 pertaining to whether the problem is of public health importance, the WG 

judged “Yes.” The rate of reported acute HepA cases in 2017 was 1.0 case/100,000 population. 

There were 1.45 cases/100,000 population among young adults aged 20-30 years compared to 

0.87 cases/100,000 population in 2016. The incidence was 2.07 cases/100,000 population 

among adults aged 30-39 years compared to 0.92 cases/100,000 population in 2016, 

representing the highest rate of HepA cases and more than double the 2016 rate for this age 

group.

In 2017, national HepA vaccine ≥2-dose coverage was 68.4% for adolescents age 13-17 years

and 1-dose coverage was 77.2%. Children living in states where routine vaccination at 12-23 

months was first recommended in 2006 who were 1 year of age in 2006, were 12-13 years old 

in 2017 when these coverage data were collected, and thus were not subject to the universal 

recommendation for children aged 12-23 months. However, coverage among these children is 

only slightly lower than the total cohort, at 61% for ≥2 doses and 71% with ≥1 dose. Despite 

catch-up vaccination being based on shared clinical decision-making, the overall coverage in 

the 13-17 year old age cohort demonstrates that catch-up vaccination is occurring.

As previously stated, the ongoing HAV outbreaks have caused a substantial number of cases, 

hospitalizations, and deaths. Among states with publicly available case information by age 

group, the median age of HAV cases is in the 30 age range, with a substantial percentage of 

cases aged in their 20s and 40s. Vaccinating adolescents who could be at risk for HAV infection 

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at present or in the future (e.g., persons who use drugs, persons experiencing homelessness, 

travelers) can have an impact on improving coverage among young adults.

In terms of Criterion 2 pertaining to how substantial the desirable anticipated effects are, the 

WG judged “Large.” HAVRIX® and VAQTA® are highly immunogenic when administered to 

children and adolescents according to multiple schedules. The immunogenicity and long-term 

protection data were mentioned earlier in this presentation. Catch-up vaccination is a way to 

increase herd immunity and ensure that the percentage of children and adolescents who miss 

vaccination as scheduled or who were born outside of the routine vaccination cohort are 

protected. Since the implementation of risk-based vaccination in adults has been poor, catch-up 

vaccination will more rapidly increase the proportion of adults with risk factors who are 

protected. HepA vaccination in childhood has demonstrated long-term protection. 

With respect to Criterion 3 regarding how substantial the undesirable anticipated effects are, the 

WG judged “Minimal.” Rates of AEs following HAVRIX®, VAQTA®, and TWINRIX® vaccination 

were similar to those seen with separately administered vaccines. No unusual or unexpected 

safety patterns were observed in VAERS for any HepA vaccines. Limited data from studies 

conducted among adults indicate that simultaneous administration of HepA vaccine with 

diphtheria, poliovirus, tetanus, typhoid, cholera, Japanese encephalitis (JE), rabies, or yellow 

fever (YF) vaccines does not decrease the immune response to either vaccine or increase the 

frequency of reported AEs. 

In terms of Criterion 4 pertaining to whether the desirable effects outweigh the undesirable 

effects, the WG judged that the intervention is favored. HepA vaccination affords long-term 

protection against HAV infection. Disease severity increases in older persons and persons who 

are immunocompromised or have CLD or other underlying health conditions. Over 20 years of 

safety monitoring have shown no known safety concerns. Earlier HepA vaccination among 

healthy children and adolescents provides protection against HAV infection before persons 

develop increased risk for HAV infection or HAV-associated complications.

Regarding Criterion 5 concerning the overall certainty of this evidence for the critical outcomes, 

there were no included studies for the effectiveness of the intervention or the safety of the 

intervention. GRADE was not used to evaluate the evidence for several reasons. HepA vaccine 

has been recommended for administration to children since 1996. HepA vaccine has been 

recommended for catch-up vaccination based on shared clinical decision-making since 2006. 

The efficacy and safety of HepA vaccines has been evaluated and well-documented. There are 

no known safety concerns with HepA vaccines based on over 20 years of use. 

With respect to Criterion 6 relating to whether the target population feels that the desirable 

effects are large relative to undesirable effects, the WG judged “Probably Yes.” In 2017, HepA 

coverage among adolescents was as previously stated, and was substantially higher than 2008 

coverage of 25.3% (≥2 doses) and 36.2% (1-dose). This demonstrates substantial catch-up 

implementation and acceptance despite a recommendation based on shared clinical decisionmaking. Although specific studies of desirability among older children or parents for HepA 

vaccine have not been conducted, the fact that almost 80% of adolescents had initiated the 

HepA vaccine series by 2017 demonstrates the demand and preference for protection against 

HepA. The HepA vaccine adolescent 2-dose coverage is comparable or greater than other 

vaccines with a routine catch-up schedule, which provides further evidence of acceptability by 

the target population.

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For Criterion 7 regarding whether there is important uncertainty about or variability in how much 

people value the main outcomes, the WG judged “Probably no important uncertainty or 

variability.” The high coverage rate, despite this recommendation being based on shared clinical 

decision-making, provides strong and consistent evidence that most parents and patients 

believe that it is as important as some routinely recommended vaccines.

Regarding Criterion 8 pertaining to whether the intervention is acceptable to key stakeholders, 

the WG judged “Probably Yes.” As previously stated, the number of states with mandates 

increased from 28% in 2011 to 44% in 2018. These states choose to achieve higher rates of 

vaccine coverage for children, even though CDC has not strongly recommended HepA vaccine 

catch-up. During the HAV multistate outbreaks, educational communications and two Health 

Alert Network (HAN) advisories have been disseminated, increasing the level of awareness 

among all clinicians and states and the general public about the threat of person-to-person 

spread of HepA and the value of a vaccine that provides lifelong protection. The HepA 

adolescent 2-dose coverage is comparable or greater than other vaccines with a routine catchup schedule which provides evidence of acceptability by key stakeholders.

With respect to Criterion 9 regarding whether the intervention is a reasonable and efficient 

allocation of resources, the WG judged “Probably Yes.” A cost-effectiveness model used to 

assess nationwide routine HepA vaccination was adapted to assess the cost-effectiveness of 

catch-up HepA vaccination and was presented during the June 2017 ACIP meeting. The 

findings of the study were that over the lifetime of the cohort, catch-up vaccination would reduce 

the total number of infections relative to the baseline by 741 while increasing doses of vaccine 

by 556,989. Across the age-cohorts, the cost-effectiveness of catch-up vaccination was most 

favorable at age 12 years due to splitting administration costs with other vaccines, resulting in 

an incremental cost-effectiveness ratio (ICER) of $189,000 per QALY gained. Catch-up was 

more effective when it was assumed to replace more adult vaccination and was targeted to 

children in late adolescence, because there is lower vaccine coverage and a higher probability 

of symptomatic disease among older children, less discounting of future costs of disease, and 

less delay in averting adult vaccination costs. The impact of vaccination on the ICER was most 

sensitive to the discount rate (3%), followed by the rate of adult vaccination.

The model had some limitations. The model was based on HepA incidence from 2008 through 

2012. The conclusions are strongly tied to factors such as vaccine uptake and disease 

transmission patterns, which may change over time and alter future cost. The model also 

excluded herd immunity effects of vaccination. The incremental costs of catch-up now would be 

more favorable, because the adolescent vaccination coverage rates are much higher than when 

this study was conducted. In 2009, 1-dose coverage was 42% and 2-dose coverage was 29.5% 

compared to 2017 coverage. Achieving 80% to 90% coverage among teens would require a 

much smaller number of additional vaccines given. In addition, the HAV incidence overall is 

higher due to the ongoing multistate outbreaks. There were 0.5 cases/100,000 population in 

2012 versus 1.0 case/100,000 population in 2017. Rates are known to be much higher in 2018 

and 2019 based on preliminary outbreak data.

Though a formal updated cost analysis was not done, a cost example is as follows for a target 

HepA vaccine series completion percentage of 80% and a target HepA vaccine series initiation 

of 90%. The example assumes that 2017 coverage rates apply to all younger adolescents who 

have higher coverage, that 100% of 1-dose recipients complete the series when calculating the 

cost of 80% completion, and that 50% of the vaccination cost is at the private price of $32.89 

and 50% at the CDC price of $20.52. To achieve 90% HepA vaccine series initiation, 3.2 million

persons would need to be vaccinated with 1 dose of HepA vaccine at a cost of $52.8 million

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(private) and $32.9 million (CDC). To achieve 80% HepA vaccine series completion, 2.2 million

additional persons would need to be vaccinated with one dose and 701,747 persons would 

need to be vaccinated with 2 doses, at a cost of $59.3M (private) and $37M (CDC).

In terms of Criterion 10 pertaining to whether the intervention is feasible to implement, the WG 

judged “Yes.” Of the 30 registries that the AIRA was able to query to test forecasting algorithms, 

27 (90%) already routinely forecast HepA vaccine as being due for an 18 year old who has 

never been vaccinated. All 30 algorithms forecast the second dose in any 18 year old who has 

had one dose. Therefore, 27 of 30 tested registries would not have to change to implement 

routine catch-up. Routine HepA catch-up already exists in states with school mandates. The 

NYC Bureau of Health recommends that all children and adolescents not previously vaccinated 

should receive the two-dose HepA vaccine series by their 19th birthday for lifetime protection.

There are opportunities to administer HepA vaccine to adolescents concurrently with vaccines 

protecting against other infections, such as HPV and Meningitis. 

A 2014 survey found that if ACIP made a recommendation for catch-up HepA vaccination at 

health maintenance visits for all children 2 to 18 years of age, 96% of pediatricians and 79% of 

family medicine physicians reported it would be very feasible to routinely assess HepA 

vaccination status and vaccinate children and adolescents who were not fully vaccinated. An 

additional 4% and 19%, respectively, indicated that it would be moderately feasible. Since then, 

increased education and awareness among providers and the public due to the ongoing HAV 

outbreaks have likely decreased barriers to vaccination. 

In terms of the balance of consequences, the WG judged that the “Desirable consequences 

probably outweigh undesirable consequences in most settings.” Regarding whether there is 

sufficient information to move forward with a recommendation, the WG judged “Yes.” With 

regard to Policy Options for ACIP consideration, the WG proposed that “ACIP recommend the 

intervention.” 

The proposed routine recommendation for children is:

 ACIP recommends hepatitis A vaccination for all children aged 12-23 months [Current]

 ACIP recommends that all children and adolescents aged 2 through 18 years who have 

not previously received hepatitis A vaccine be vaccinated at any age (i.e., children and 

adolescents are recommended for catch-up vaccination) [Proposed]

Turning to the potential addition of PWHIV to the list of groups at increased risk of HAV or 

severe HAV disease, the following policy question and PICO were presented to ACIP in 

February 2019 and are as follows, “Should routine two-dose* vaccination to prevent HepA virus 

infection be given to HIV-positive persons? *Or three-dose when combination vaccine is used?” 

The population was adult HIV-positive persons regardless of another indication for vaccination. 

The intervention was routine two-dose HepA vaccination. The comparison was no routine twodose HepA vaccination. The outcomes of interest were HepA infection, mild AEs, and SAEs. 

In terms of background, at the end of 2016, an estimated 1.1 million people aged 13 years and 

older had HIV infection in the US1. When PWHIV are co-infected with HepA virus infection, they 

experience higher HAV viral loads and a prolonged duration of HepA viremia than persons 

without HIV infection2,3. In addition, HAV infection has the potential to increase HIV viral loads 

and HIV transmission. PWHIV respond to HepA vaccine with a seroconversion rate of 48.5% to 

93.9% following a 2-dose monovalent vaccine schedule, and factors associated with a 

protective antibody response in PWHIV include a CD4 cell count greater than 200 cells/mm3

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and a low HIV RNA viral load4,5 [1CDC. HIV Surveillance Supplemental Report 2019;24(1); 

2Puoti, M., et al. Semin Liver Dis (2012) 32(02): 103-113; 3Gallego, M., et al. Journal of the 

International Association of Physicians in AIDS Care, vol. 10, no. 1, Jan. 2011, pp. 40–42; 

4Weissman, S. , Feucht, C. and Moore, B. A. (2006), Journal of Viral Hepatitis, 13: 81-86; and 

5Mena, G et al. Human vaccines & immunotherapeutics vol. 11,11 (2015): 2582-98]. 

In 2017, the number of new HIV diagnoses was 38,739 and these were mostly among adults.

The highest numbers were among adults ages 20-39 years. CDC classifies HIV diagnoses into 

transmission categories to which transmission may be attributed. Based on this classification, 

approximately 76% of persons living with HIV already have another risk group for which HepA 

vaccination is recommended. The MMP, which looks at a nationally representative sample of 

persons living with HIV, was used to answer the question, “What percentage of PWHIV do not 

have an existing risk factor for which HepA vaccine is recommended?” The percentage of 

persons living with HIV without a recommended risk group for HepA vaccination is higher when 

looking at more specific risk factor data. MMP estimates that 59.9% (95% CI: 57.3 - 62.4) of 

PWHIV had a risk factor of MSM, injection or non-infection drug use, CLD, clotting-factor

disorder, or homelessness in the past 12 months. Data were not available for proportions of 

PWHIV with occupational risk, travel, or close contact with an international adoptee. Excluding 

these groups, 40.1% (95% CI : 37.6-42.7%) of PWHIV in the US do not have an ACIP 

recommended indication for HepA vaccine.

GRADE and the EtR Framework were presented during the February ACIP meeting. The 

GRADE summary is as follows. The benefit outcome, HepA infection, for RCTs was graded as 

an Evidence Type 2. This was downgraded for indirectness due to variability of HepA antibody 

seroconversion thresholds used. The benefit outcome, HepA infection, for observational studies 

was graded as an Evidence Type 4. This was downgraded for indirectness due to variability of 

HepA antibody seroconversion thresholds used and for risk of bias due to limited studies 

comparing a 2-dose standard intervention to no vaccine. The harm outcome, mild AEs, for 

RCTs was graded as an Evidence Type 1. The harm outcome, mild AE, for observational 

studies was graded as an Evidence Type 3. The harm outcome, SAEs, for RCTs was graded as 

an Evidence Type 3. This was downgraded for imprecision due to small study population size.

The harm outcome, SAEs, for observational studies was graded as an Evidence Type 4. This 

was downgraded for imprecision due to small study population size. The WG judged that the 

“Desirable consequences probably outweigh undesirable consequences in most settings.” For 

Policy Options for ACIP Consideration, the WG proposed that “ACIP recommends the 

intervention.” 

In terms of additional information regarding HAV infection among PWHIV, among people with a 

diagnosis of HIV who received outpatient HIV medical care during 2014-2017, the prevalence of 

a diagnosis of HepA recorded in the medical record at the primary HIV care site during a 2-year 

period was 0.48% (95% CI=0.26-0.70). Regarding additional information pertaining to HAV 

outbreaks and PWHIV, HIV co-infection outbreak data are available for a limited number of 

states. Among 249 reported cases of HAV in Tennessee, 11 (4%) patients were PWHIV. Among 

359 reported cases of HAV in Massachusetts, 14 (4%) were PWHIV. Among 85 reported cases 

of HAV in Illinois, 7 (8.2%) were PWHIV. This shows a clear excess of HAV infection risk among 

PWHIV. The US population estimate is 327 million, with PWHIV comprising less than 0.34% of 

the general US population. 

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Several questions were asked by ACIP during the February 2019 meeting. Dr. Nelson provided 

explanations for the following selected questions: 

 Is there value in knowing laboratory criteria before administering the vaccine? Should antiHAV titers be checked periodically after vaccine administration? Will CD4 count thresholds 

be utilized for the recommendation of HepA vaccination among PWHIV?

 What are the costs of vaccinating PWHIV?

Since response to vaccine might be reduced in PWHIV who are immunosuppressed (lower CD4 

counts), post-vaccination testing is proposed to be recommended for all PWHIV at least 1 

month after vaccination. Although patients with lower CD4 counts may not respond as well to 

the vaccine, in order to avoid missed opportunities to immunize, immunization against HepA 

should not be delayed until the CD4 count exceeds a particular threshold. PWHIV who do not 

respond to vaccine should be considered susceptible to HAV infection and counseled about 

precautions to prevent HAV infection and the need to obtain IG post-exposure prophylaxis

(PEP) for any known or likely exposure to an HAV infected person.

The cost of adult vaccines are approximately $30 CDC cost and $68 private cost. Vaccine 

administration fees range from a few dollars up to $20 based on the best available information. 

Regarding how much it would cost to vaccinate PWHIV, a formal cost-effectiveness analysis 

was not done for PWHIV as a risk group for HepA vaccination. Considering that about 400,000 

PWHIV are potentially unvaccinated against HepA vaccine, a very basic calculation, assuming 

50% vaccine uptake, is as follows: 200,000 X $68 (1 dose) = $13.6 million; 200,000 X $136 (2 

doses) = $27.2 million, in addition to a small administration fee. There are a number of other 

considerations as well. Not all PWHIV will be vaccinated at the same time and the cost would be 

spread out over time. Vaccination in this high risk population would help disrupt outbreaks by 

providing increased herd protection. In an outbreak response, the associated costs, including 

health care expenses and deferred activities, are substantial.

The proposed recommendation for PWHIV is as follows: 

 ACIP recommends that all persons with HIV aged ≥1 year be vaccinated with HepA 

vaccine. 

Moving to the pregnancy update, pregnancy has been on the Recommended Adult 

Immunization Schedule by Medical Condition and Other Indications since 2005-2006 if another 

risk factor is present. A review of the published data on HepA during pregnancy1 found that

HepA infection during pregnancy is associated with gestational complications (e.g., preterm 

labor, placental abruption, premature rupture of membranes)2. Generally, infants born to 

mothers with HAV infection are healthy, but there are rare exceptions. There is no increased 

risk of maternal or infant mortality after HepA vaccination in pregnancy [1Chaudhry SA, Koren G. 

Hepatitis A infection during pregnancy. Can Fam Physician 2015;61:963-964; 2Elinav E, BenDov IZ, Shapira Y, Daudi N, Adler R, Shouval D, Ackerman Z. Acute hepatitis A infection in 

pregnancy is associated with high rates of gestational complications and preterm labor. 

Gastroenterology. 2006 Apr;130(4):1129-34].

A VAERS study by Moro et al in 2014 based on VAERs reports of AEs in pregnant women who 

received HepA or HepAB vaccine from January 1, 1996 to April 5, 2013 found no unusual 

clustering of birth defects. VAERS received 139 reports of AEs in pregnant women. Of those, 7 

(5.0%) were classified as serious, 65 (46.8%) did not describe any AEs, and no maternal or 

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infant deaths were identified. The review of VAERS reports concluded that no concerning 

pattern of AEs in pregnant women or their infants following maternal HepA or HepAB 

immunizations during pregnancy was identified [Moro PL, Museru OI, Niu M, et al. Reports to 

the Vaccine Adverse Event Reporting System after hepatitis A and hepatitis AB vaccines in 

pregnant women. Am J Obstet Gynecol 2014;210:561.e1-6].

Preliminary results of a large, ongoing retrospective cohort study in the VSD were presented to 

the WG. Among pregnancies ending in live births, HepA vaccine was not associated with 

common maternal and infant AEs, but a potential signal for small for gestational age (SGA) 

births was identified. The observed effect size for SGA was an absolute difference of 4%, or 

12.3% in vaccine exposed versus 8.3% in vaccine unexposed. General US prevalence 

estimates for SGA are approximately 10% and up to 14% among women of Asian race, who 

comprised 30% of the vaccine exposed group in the study. The investigators and the WG

considered that this SGA finding was likely due to unmeasured confounding, and was unlikely to 

be clinically meaningful. This study is expected to be published later this year [Unpublished VSD 

data].

The 2006 Hepatitis Vaccine Statement indicated that data on pregnancy were lacking and as 

such, no recommendation was made. The proposed HepA recommendation for pregnant 

women, which is consistent with the vaccine schedule and is parallel to the HepB vaccine 

recommendations, follows:

 ACIP recommends that: 

– 

–

Pregnant women who are identified as being at risk for HAV infection during 

pregnancy or for having a severe outcome from HAV infection (e.g., travelers, 

persons who use injection and non-injection drugs, persons who have 

occupational risk for infection, persons who anticipate close personal contact with 

an international adoptee, persons experiencing homelessness, persons with 

chronic liver disease, PWHIV) should be vaccinated during pregnancy if not 

previously vaccinated [Proposed]

Pregnant women who are not vaccinated against HAV infection during pregnancy 

should be counseled concerning other methods to prevent HAV infection 

[Proposed]

Regarding clotting-factor disorders proposed for removal as a recommendation, persons who 

have clotting-factor disorders have been recommended to receive the HepA vaccine since 

19961. However, the risk of HAV infection has decreased over time, and the risk for viral 

transmission for persons with clotting-factor disorders is considered the same as that for the 

general population2. In the US, >80% of persons with hemophilia are treated with recombinant 

clotting-factor concentrates, which are sterilized (e.g., pasteurization, heat inactivation, filtration) 

enabling these factors to be safe2. Previously, some processes focused only on treatment with 

solvents/detergents which inactivated lipid-enveloped viruses3, but not non-enveloped viruses, 

such as HAV, resulting in a risk for HAV infection4. Secondary virus reduction steps are now 

common2,5,6 [1Fiore AE, Wasley A, Bell BP. MMWR Recomm Rep 2006;55:1-23; 2Klamroth, R., 

Gröner, A. and Simon, T. L. (2014), Transfusion, 54: 1406-1417; 3Tabor, E. (1999), Transfusion, 

39: 1160-1168; 4Mannucci PM, Gdovin S, Gringeri A, et al. Ann Intern Med 1994;120:1–7; 

5GRÖNER, A. (2008), Haemophilia, 14: 54-71; and 6US Food and Drug Administration. Guide to 

inspections of viral clearance process for plasma derivatives. 2009. [cited 2013 Jan 25]. 

Available from: https://ntrl.ntis.gov/NTRL/dashboard/searchResults/titleDetail /PB98137144.

xhtml].

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During 1992-1993, several outbreaks of HepA were reported in Europe among persons who 

had clotting-factor disorders who had been administered solvent detergent-treated factor VIII 

concentrates that presumably had been contaminated from plasma donors incubating HAV1. In 

the US, data from one serologic study published in 1994 suggested that hemophilic patients 

may be at increased risk for HAV infection2. During 1995-1996, several patients who had 

clotting-factor disorders reportedly developed HepA after having been administered solventdetergent-treated factor VIII and factor IX concentrates3 [1Mannucci PM, Gdovin S, Gringeri A, 

et al. Ann Intern Med 1994;120:1–7; 2Mah MW, Royce RA, Rathouz PJ, et al. Vox Sang 

1994;67(suppl 1): 21–2; and 3CDC. MMWR 1996;45:29–32]. 

The clotting-factor recommendations from the 2006 ACIP Hepatitis A Vaccine Statement kept 

part of the 1996 recommendations, “Susceptible persons who are administered clotting-factor 

concentrates, especially solvent-detergent-treated preparations, should receive hepatitis A 

vaccine.” The 2006 recommendation added that, “Changes in clotting-factor preparation 

practices and donor screening have greatly reduced the risk for hepatitis A for recipients of 

clotting-factors.” 

The ACIP Hepatitis Vaccines WG received input from the FDA and reviewed the literature on 

HAV infection among persons with clotting factor disorders. No case studies of HepA infections 

among US persons with clotting-factor disorders were found in the literature in the last 20 years

[Soucie JM, Robertson BH, Bell BP, et al. Hepatitis A virus infections associated with clotting 

factor concentrate in the United States. Transfusion 1998;38:573-9]. 

The WG considerations are as follows. Persons who have clotting-factor disorders has been a 

risk group for HepA vaccination since 1996. The risk of HAV infection has decreased over time, 

and persons with clotting factors are currently at an extremely low risk for infection with HAV. No 

case study has been reported for any person in the US infected with HAV after exposure to 

clotting factors in 20 years1. Secondary virus reduction steps are now common instead of 

solvent-detergent treated. Many of the clotting factors now in use are recombinant factors.

Source plasma is now screened for HAV2. There is no longer a specific risk of HepA virus 

infection associated with clotting-factor disorders; therefore, this group may be removed from 

consideration as part of a high risk population for whom HepA vaccination is specifically 

recommended [1Soucie JM, Robertson BH, Bell BP, et al. Transfusion 1998;38:573-9; 2Gröner, 

A. (2008). Haemophilia, 14: 54-71]. 

In closing, Dr. Nelson recapped the proposed recommendations:

Recommendation #1: Proposed Routine Recommendation for Children

ACIP recommends hepatitis A vaccination for all children aged 12-23 months [Current; Revise]

ACIP recommends that all children and adolescents aged 2 through 18 years who have not 

previously received hepatitis A vaccine be vaccinated at any age (i.e., children and adolescents 

are recommended for catch-up vaccination) [Proposed].

Discussion Points

Regarding the balance of consequences and the WG’s “Probably Yes,” Dr. Atmar inquired as to 

what detracted from a definitive “Yes” and what the concerns were of the WG that weighed in as 

a “Probably Yes.”

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Dr. Nelson indicated that the WG deliberation was about being more conservative and saying 

“Probably Yes” instead of “Yes” due to the past cost-effectiveness analysis that was presented. 

The WG was unanimous in agreeing that the catch-up vaccination should be proposed to be 

recommended.

Dr. Moore added that there was no hesitation about this whatsoever on the WG. Everyone was 

unanimously and strongly in favor of a routine recommendation for catch-up. In fact, they had a 

conversation about which box to tick. The thought on the WG was that if they were so definitive, 

they would probably get questions from the full committee about why they were so definitive. In 

fact, no concerns were expressed. They felt that the economic analysis conducted in 2014 no 

longer reflects the current conditions. While no formal economic analysis was done, the WG 

knew that things would be much more favorable currently than they appeared in 2014.

Dr. Messonnier pointed out that typically when they get to this point, the evidence framework 

simplifies it though they have talked about it so much. Since the last time they assessed this, 

there has been an increase in large HepA outbreaks. In the cases, 40% of the patients do not 

have an identifiable risk factor. Even though the current intervention for the current outbreaks is 

more targeted toward adults because that is where the risk groups are and likely will be 

controlled with the intervention, there is an upcoming cohort of children and HepA is cyclical. As 

they approach adulthood, another cycle of outbreaks would be expected. The goal is to catch 

them up on vaccination at a time when it is known they are more likely to seek medical care, 

with the expectation that the vaccine will last long enough that when they reach their risk period, 

they will then be protected.

Dr. Moore added that the WG’s great concern was that the longstanding risk-based 

recommendations for adults have been poorly implemented for many reasons. Many of the 

adults who find themselves at risk later on are often those with poor access to healthcare and 

utilization of health services. This vaccine can provide long-term, possibly lifelong, protection. 

There is now an opportunity to have the entire cohort cared for before they become adults and 

acquire or express risk factors. That was the strong motivation of the group.

Dr. Hunter emphasized that this was another example, along with HPV and pneumococcal 

conjugate vaccine, of the importance of vaccinating children to protect adults. He wanted to 

make sure that they were clear that this catch-up recommendation would not detract in any way 

from the young childhood routine vaccination recommendation.

Dr. Moore responded that close to 80% of teens already have initiated the series, and there are 

many opportunities now for immunization during adolescence when catch-up can occur. The 

WG had the conversation and discussed whether there should just have a blanket HepA 

vaccination sometime before becoming 18. There was a strong feeling that the routine 

recommendation that children should be vaccinated at the earliest opportunity to protect them 

should be maintained, which as 12 months to 23 month of age. The proposed recommendation 

would be only for children who missed out on that opportunity. In fact, the current cohort were 

not subject to that routine recommendation in early childhood. They were caught up over time in 

many cases, but were not subject to the original recommendation.

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Dr. Maldonado (AAP) indicated that she is a pediatrician who went through some of those early 

days, especially in California where they had the risk-based vaccination. It was extremely 

confusing for pediatricians to determine which children were actually high risk and should be 

vaccinated. She thought it had to do with the incidence in the county, so it was very 

complicated. She thought this was a great opportunity to stem a fatal disease that is easily 

preventable, and that the recommendation would be helpful for adult internists and 

pediatricians.

Noting that it had been a long time since ACIP had reviewed the economic models, Dr. Lee 

thought that the ICERs looked much better if herd immunity was accounted for. This is a holistic 

program that is actually capturing adolescents and avoiding the need to track down high risk 

adults. At least in terms of the economic analysis, she was confident that this would be a very 

cost-effective recommendation.

Dr. Szilagyi also wondered why the WG did not select a definitive “Yes,” because it seemed 

definitive to him. He also was impressed with the feasibility data that Dr. Nelson presented. He 

asked why a formal economic analysis was not performed.

Dr. Nelson indicated that the cost-effectiveness analysis was presented in June 2017; however, 

it was not updated to represent the changing epidemiology.

Dr. Walter said that as a general pediatrician who has administered catch-up vaccination for a 

number of years, he was glad to see that they were moving forward with a full recommendation 

to administer catch-up vaccination. One thing that was curious to him was the disparity between 

second dose coverage in teens versus younger children, with a much narrower gap in the older 

adolescents.

Dr. Nelson indicated that they believe it is due to under-estimation of 2-dose coverage in the 

younger group 19 months through 35 months of age. If children are vaccinated close to 23 

months and they can be vaccinated up to 18 months for the second dose, they might be missed 

in that survey.

Dr. Moore moved to accept the proposed recommendation for routine catch-up vaccination for 

children as written. Dr. Walter seconded the motion. There was no further discussion.

Recommendation #2: Proposed Recommendation of HepA Vaccine for Persons with HIV

The full risk-based recommendations are shown here. It is proposed to remove “persons with 

clotting-factor disorders” as a recommendation, add PWHIV as being at increased risk, and 

update persons with CLD.

Persons At Increased Risk for HAV Infection

– 

– 

–

– 

– 

– 

– 

Persons traveling to or working in countries that have high or intermediate endemicity of 

Infection. 

Men who have sex with men (MSM)

Persons who use injection or non-injection drugs

Persons who have occupational risk for infection

Persons who anticipate close contact with an international adoptee

Persons experiencing homelessness 

Persons with clotting factor disorders (remove)

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Persons At Increased Risk For HAV Associated Complications

– 

–

Persons with HIV [Vote 2]

Persons with chronic liver disease [update] 

Any person wishing to obtain immunity

The language for Vote #2 is:

ACIP recommends that all persons with HIV aged ≥1 year be vaccinated with hepatitis A 

vaccine. 

Discussion Points

Related to the proposal to perform post-vaccination serologic testing at least 1 month after 

vaccination, Dr. Atmar wondered what would be done with that information should a person be 

seronegative and whether there would be a proposal to boost. Conversely, there already is a 

prevalence of seropositivity in persons with HIV who presumably would not be at risk and would 

not require vaccination. In that case, he wondered whether there was consideration for 

screening for seropositivity and only vaccinating those who are seronegative, or if that was not 

thought to be worthwhile from a cost-benefit perspective.

Dr. Nelson indicated that for post-vaccination testing of those who are not positive, the proposal 

is to counsel that person about risk of exposure and inform them that they would need IG in 

case they were exposed or concerned about exposure and the potential for revaccination. 

However, the WG was just giving clinical guidance on that versus proposing to recommend that 

there would be continued revaccination. Regarding pre-exposure testing, that should not deter 

or preclude vaccination in those who could not be tested.

Dr. Walter requested clarification regarding whether testing would be done after series 

completion, which Dr. Nelson confirmed.

Dr. Romero asked how much additional cost testing would add to the figures for cost of 

vaccination. 

Dr. Nelson indicated that the cost of antibody testing is approximately $30, though she said she 

would have to verify that.

Dr. Atmar thought it was probably $30 to $50, but the point was that if there is high 

seroprevalence, this would be cost-saving because they would not be vaccinating. If there was 

low seroprevalence, there would be added costs. However, averting unnecessary vaccination 

potentially could be cost-saving.

Dr. Moore indicated that the WG had conversations about this, but did not feel that it could be 

provided as clinical guidance rather than having the ACIP weigh in on it. It will depend upon the 

patient population. There is not a uniform answer for everyone who has HIV. In certain clinical 

settings, it may be convenient and easy to screen in advance and they may do that. However, 

the WG did not want this to be perceived as any kind of barrier to immunization if routine 

immunization already was going to be done. The other thing about post-vaccine serologic 

testing is that it was intended to harmonize with the HepB post-vaccine serologic testing that is 

already recommended for these individuals after they receive the HepB series. The idea was 

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that this could be tagged on at the same time. The WG did not have data to recommend booster 

doses, so they did not address this.

Dr. Messonnier pointed out that perhaps there was a language issue on Slide 59 in the first 

bullet stating, “. . . proposed to be recommended for all PWHIV at least 1 month after 

vaccination” in that it sounded like a recommendation rather than clinical guidance.

Dr. Nelson indicated that this was addressed with the statement language on Slide 85 in the first 

bullet stating, “Testing for the presence of anti-HAV antibody after vaccination is recommended 

for the persons whose subsequent clinical management depends on knowledge of their immune 

status: PWHIV, and other immunocompromised persons (e.g., hematopoietic stem-cell 

transplant recipients, persons receiving chemotherapy),” the second bullet stating, “Testing 

should be performed at least one month after administration of the final dose of the vaccine 

series with total anti-HAV or IgG anti-HAV assays,” and the third bullet stating, “Persons who do 

not respond immunogenically to vaccination should be considered susceptible to HAV infection 

and counseled about precautions to prevent HAV infection and the need to obtain IG postexposure prophylaxis for any known or likely exposure to a HAV infection.”

Dr. Messonnier did not feel that the language was correct, given that it was clinical guidance 

versus recommended. While ACIP was not being asked to vote on this language, she thought 

there was a way to articulate the language to more clearly indicate that it was clinical 

consideration versus a recommendation.

Dr. Cohn added that ACIP members were sent a draft of this document, but there was still 

plenty of time to incorporate some of these comments and address those even if they voted to 

approve the statement during this meeting.

Dr. Lee was fully in favor of thinking about this population as one that they should be targeting. 

With that said, she thought modeling would have been helpful in this instance to have given 

them more insight into the questions that Dr. Atmar raised and because it was incorporating 

clinical guidance pertaining to testing and clarifying what the benefit would be. This is a small 

population that has been involved in outbreaks, so from an outbreak perspective this is very 

important. However, she did not feel that this would affect her voting decision.

Dr. Stephens indicated that he too had concerns about the post-vaccination language to some 

degree. However, his question regarded what would occur with revaccination in those 

individuals. The lack of data on revaccination seemed like an opportunity.

Dr. Moore made a motion to accept the second recommendation that all persons with HIV aged 

≥1 year be vaccinated with HepA vaccine as proposed. Dr. Ault second the motion.

Dr. Talbot noted that the proportion of the HIV population who do not respond may not respond 

because they have not had reconstitution of their immune system. To her, it would seem 

reasonable once they have return of immune function to try vaccination again. In anticipation of 

receiving this question a lot from HIV providers, she suggested including something in the 

clinical guidance section to that effect. Providers also are likely to ask how many times they 

should try, so she suggested including guidance about that as well. 

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Recommendation #3: ACIP Affirmation of the Updated Statement “Prevention of Hepatitis 

A Virus Infection in the United States: Recommendations of the Advisory Committee on 

Immunization Practices” with respect to the following:

PWHIV Clinical Guidance

– 

– 

– 

– 

Since response to vaccine might be reduced in PWHIV who are immunosuppressed, 

post-vaccination testing is recommended for all PWHIV at least 1 month after 

vaccination

Although PWHIV with lower CD4 cell counts or percentages may have reduced 

response to the vaccine, in order to avoid missed opportunities to immunize, 

immunization against hepatitis A should not be delayed until the CD4 cell count exceeds 

a particular threshold 

PWHIV who do not respond to vaccine should be considered susceptible to HAV 

infection and counseled about precautions to prevent HAV infection and the need to 

obtain IG post-exposure prophylaxis for any known or likely exposure to HAV

PWHIV who received hepatitis A vaccine should be counseled that the vaccination 

against hepatitis A infection may not provide long term protection and they may need to 

obtain IG after a high risk HAV exposure (e.g., sexual or household contact) 

Persons with Chronic Liver Disease [Update]

ACIP recommends that: 

̶ Persons with chronic liver disease (including, but not limited to, persons with hepatitis B 

virus infection, hepatitis C virus infection, cirrhosis, fatty liver disease, alcoholic liver 

disease, autoimmune hepatitis, and an alanine aminotransferase [ALT] or aspartate 

aminotransferase [AST] level greater than twice the upper limit of normal) should be 

routinely immunized against hepatitis A. [Proposed]

Hepatitis A Vaccine Recommendation for Pregnant Women

ACIP recommends that: 

̶ Pregnant women who are identified as being at risk for HAV infection during pregnancy 

or for having a severe outcome from HAV infection (e.g., travelers, persons who use 

injection and non-injection drugs, persons who have occupational risk for infection, 

persons who anticipate close personal contact with an international adoptee, persons 

experiencing homelessness, persons with chronic liver disease, PWHIV) should be 

vaccinated during pregnancy if not previously vaccinated [Proposed]

̶ Pregnant women who are not vaccinated against HAV infection during pregnancy should 

be counseled concerning other methods to prevent HAV infection [Proposed]

Implementation Strategies

Settings Providing Services to Adults (NEW)

̶ Settings in which a high proportion of persons have risk factors for HAV infection (e.g., 

health care settings targeting services to people who use injection or non-injection 

drugs, group homes and nonresidential day care facilities for developmentally disabled 

persons). A health care provider (HCP) may assume that unvaccinated adults age ≥19 

years are at risk for HAV infection and offer hepatitis A vaccination without individual 

risk-factor screening if they have not previously completed vaccination 

̶ Hepatitis A vaccination may be offered in outreach and other settings in which services 

are provided to persons at risk for HAV infection (e.g., homeless shelters, syringe 

service programs) 

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̶ HCP should consider implementing standing orders to identify adults recommended for 

hepatitis A vaccination and administer vaccination as part of routine services

̶ Vaccination of staff should be considered in facilities where hygiene is difficult to 

maintain (e.g., group homes for developmentally disabled)

Hepatitis A Vaccination During an Outbreak [Update] 

ACIP recommends that:

̶ All unvaccinated children aged ≥1 year and adults age ≥19 years who are at risk for HAV 

infection (e.g., persons who use injection or non-injection drugs, persons experiencing 

homelessness) should receive one dose of hepatitis A vaccine during a hepatitis A 

outbreak [Proposed]

̶ In the event of a community outbreak propagated by person-to-person transmission, 

public health officials should consider recommending administration of pre-exposure 

hepatitis A vaccination in close congregate settings providing services to high risk 

persons in the vicinity of the outbreak (e.g., persons incarcerated in correctional 

facilities, health care settings targeting services to people who use injection or noninjection drugs, homeless shelters, syringe service programs) due to the risk of an 

outbreak in these settings and increased risk of HAV infection among persons in these 

settings [Proposed]

Prevaccination Serologic Testing [Update]

– 

– 

– 

– 

– 

– 

– 

– 

– 

Prevaccination serologic testing for hepatitis A immunity prior to vaccination is not 

recommended, but may be considered in specific settings as a way to reduce costs by 

not vaccinating persons who are already immune [Update]

Prevaccination serologic testing should not be a barrier to vaccination of susceptible 

persons, especially in populations that are difficult to access [Update] 

If prevaccination serologic testing is performed, commercially available tests for total 

anti-HAV or IgG anti-HAV should be used [Update]

Antibody production in response to HAV infection results in lifelong immunity to hepatitis 

A and, presumably, to HAV infection 

Prevaccination serologic testing of children is not indicated because of their expected 

low prevalence of infection 

Persons for whom prevaccination testing will likely be most cost-effective include adults 

who were either born in or lived for extensive periods in geographic areas that have a 

high or intermediate endemicity of HAV; and adults in certain population groups; 

American Indians, Alaska Natives, and Hispanics 

In populations that are expected to have high rates of previous HAV infection, 

vaccination history should be obtained where feasible prior to testing or vaccination 

[Update]

Vaccinations should not be postponed if vaccination history cannot be obtained, if 

records are unavailable or if prevaccination testing is not feasible [Update]

Vaccination of a person who is immune because of previous infection does not increase 

the risk for adverse events from vaccination

Postvaccination Serologic Testing [Update]

– 

– 

Testing for the presence of anti-HAV antibody after vaccination is recommended for the 

persons whose subsequent clinical management depends on knowledge of their 

immune status: PWHIV, and other immunocompromised persons (e.g., hematopoietic 

stem-cell transplant recipients, persons receiving chemotherapy) [Update]

Testing should be performed at least one month after administration of the final dose of 

the vaccine series with total anti-HAV or IgG anti-HAV assays [Update]

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– 

– 

– 

– 

141

Postvaccination testing is not indicated for other persons because of the high rate of 

hepatitis A vaccine response among children and adults 

Persons who do not respond immunogenically to vaccination should be considered 

susceptible to HAV infection and counseled about precautions to prevent HAV infection 

and the need to obtain IG post-exposure prophylaxis for any known or likely exposure to 

a HAV infection [Update]

Revaccination [New]

Revaccination (i.e., booster dose, challenge dose, or revaccination with a complete 

series) is not generally recommended for persons with a normal immune status who 

were vaccinated as infants, children or adults (Theeten 2015, Spradling 2016, Mosites 

2018) 

Anti-HAV long-term persistence studies do not indicate a need for additional hepatitis A 

vaccine doses beyond the 2-dose primary vaccine series or 3-dose series if combination 

Hepatitis A-Hepatitis B vaccine was administered

For other immunocompromised persons (e.g., PWHIV, hematopoietic stem-cell 

transplant recipients, persons receiving chemotherapy), the ACIP has no specific 

guidance because limited data are available to determine the need for booster doses or 

revaccination with a complete series 

Other Guidance

̶ Interrupted Schedules and Minimum Dosing Intervals

̶ Other Immunization Management Issues and Considerations

The language in these two sections is consistent with previously published recommendations 

and in best practices guidance at ACIP.

Discussion Points

Dr. Ault asked whether there was a registry study about pregnancy in the HepA vaccine a 

couple of decades ago when it was new.

Dr. Nelson indicated in 1998, FDA published a general population two-year review of HepA 

vaccine using VAERS data that found few unexpected HAV vaccine–associated SAEs after the 

use of at least 6 million vaccine doses in the US. She did not present these data during this 

session because it was used as evidence for the 2006 recommendations. GSK has a

TWINRIX® pregnancy registry. 

Dr. Cohn requested that when the pregnancy language is updated, language be included about 

the catch-up recommendation for adolescents younger than 18 who are pregnant.

Dr. Hahn (CSTE) pointed out that every case of HepA in the US in theory is investigated by 

local health departments and is reported to CDC. She wondered whether state health 

departments were queried to determine whether they had reported any cases of clotting-factor 

disorder since not every case gets published.

Dr. Nelson replied that while they did not query state health departments, they did work closely 

with the FDA to determine whether there had been any reports.

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Related to the EtR framework for HIV that was included in the background documents, Dr. Lee 

asked whether the criteria for resource use could be updated and marked as “Uncertain” as she 

felt that it would more accurately reflect the information currently available. She was thinking 

about the consistency by which they apply these criteria across recommendations, and that 

perhaps they should identify that a revised version of the cost-effectiveness model was not done 

to answer that specific question. While she felt comfortable that it would be cost-effective, she 

still thought that this should be changed to “Uncertain” versus “Probably Yes.”

Dr. Moore indicated that the WG would be happy to consider that and thanked Dr. Lee for the 

feedback, pointing out that this is a learning process for all of them as they navigate how to use 

this framework consistently. With respect to Dr. Hahn’s point, she thought the primary issue in 

conversations the WG had with FDA was that it was understood that the problem with clottingfactors themselves have been addressed and that, therefore, the risk of exposure from having a 

clotting-factor disorder no longer exists. It was not just that the WG did not find anything.

Dr. Hahn (CSTE) pointed out that the data showed greater than 80%, so it does not sound like 

100% are using recombinant material. She also reminded everyone that the state health 

department is a great data source that CDC may not always think to check. These cases are 

investigated, there are great data, and they do not often hear it even mentioned that they looked 

at their own data.

Dr. Moore made a motion to affirm the updated statement “Prevention of Hepatitis A Virus 

Infection in the United States: Recommendations of the Advisory Committee on Immunization 

Practices.” Dr. Frey seconded the motion.

Dr. Hunter commended the WG on trying to harmonize as much as possible, particularly with 

HepB, and for harmonizing medical condition definitions between different recommendations for 

different vaccines as much as possible. He believes that practicing clinicians will be appreciative 

of that.

Dr. Bernstein noted that there was language about recommendations for HepA vaccine during 

an outbreak that mentioned children aged ≥1 year of age. Now that ACIP is recommending 

HepA vaccine for 6 months through 11 months for those traveling outside of the US to certain 

areas, he wondered whether they should be making the same recommendation in an outbreak 

situation.

Dr. Moore indicated that the WG did not consider a recommendation for vaccination below the 

licensed age for children who are in communities where outbreaks occur. They recommended it 

for travel because MMR vaccine also is given at 6 months to 11 months of age prior to 

international travel. Normally, HepA IG would be given because it is not a licensed product 

below a year of age. In that case, they recommended the vaccine instead if protection against 

HepA was necessary because HepA IG cannot be given with MMR vaccine at the same time 

because it interferes with measles protection. For a number of reasons, ACIP did not

recommend the vaccine for ages for whom it is not licensed in outbreak settings in the US.

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Dr. Messonnier added that the other part of that regarded whether children ≥1 year of age are at 

risk of HepA in the ongoing outbreaks.

Dr. Moore said that the outbreaks that are spreading from person-to-person are occurring 

among adults. Symptomatic HepA is extremely rare in an infant. They may become a passive 

transmitter or may be infected, but they do not get sick. Since there is not a health threat to 

those infants, protection of the adults is the focus.

Dr. Romero said that he has been on ACIP for 5 years and thanked Dr. Nelson for shepherding 

numerous changes to HepA and updating it.

Dr. Quach (NACI) asked whether in the CLD component they were talking about including 

people with an alanine aminotransferase (ALT) or aspartate aminotransferase (AST) level 

greater than twice the upper limit of normal, which seemed low to her in clinical day-to-day work.

Dr. Nelson indicated that the language paralleled the HepB vaccine statement and was 

deliberated on by the sitting WG a number of times.

Dr. Atmar said that they see a lot of patients who have an acute illness whose ALT is more than 

twice normal, so that language gave him pause as well. It seemed to him that there should be 

some chronicity associated with an elevated ALT and not in the setting of an adverse drug 

reaction or acute illness. Perhaps that could be included as a consideration, but it should not 

prompt a clinician to think they have to give the vaccine.

Dr. Moore indicated that the WG would be glad to take that into consideration. It was not 

intended for a temporary blip because of an acute illness. It is for an ongoing condition in the 

same way it was meant for a HepB vaccination.

Motion/Vote #1: Hepatitis A Vaccine Catch-Up 

Dr. Moore made a motion to approve the recommendation that all children and adolescents 

aged 2 through 18 years who have not previously received hepatitis A vaccine be vaccinated at 

any age (i.e., children and adolescents are recommended for catch-up vaccination). Dr. Walter

seconded the motion. No COIs were declared. The motion carried with 14 affirmative votes, 0 

negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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Motion/Vote #2: Hepatitis A Vaccine for Persons with HIV 

Dr. Moore made a motion to approve the recommendation that all persons with HIV aged ≥1 

year be vaccinated with hepatitis A vaccine. Dr. Ault seconded the motion. No COIs were 

declared. The motion carried with 14 affirmative votes, 0 negative votes, and 0 abstentions. The 

disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Motion/Vote #3: Updated Statement 

Dr. Moore made a motion to affirm the updated statement “Prevention of Hepatitis A Virus 

Infection in the United States: Recommendations of the Advisory Committee on Immunization 

Practices”. Dr. Frey seconded the motion. No COIs were declared. The motion carried with 14 

affirmative votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as 

follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Updates: Hepatitis A Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch indicated that the purpose of this resolution was to streamline the Recommended 

Vaccination Schedule and Intervals section, update the language related to catch-up 

vaccination, add information about the accelerated Twinrix® schedule, clarify the timing of 

vaccine and immunoglobulin receipt, and remove pregnancy as a precaution. Yellow 

highlighting is used to indicate changes to the resolution in comparison to the prior approved 

version.

Eligible groups remain unchanged, which includes infants 6-11 months of age traveling to 

countries outside of the US for which protection against hepatitis A is recommended and all

children aged 1 through 18 years of age.

For the Recommended Vaccine Schedule, the primary change is in the catch-up language. In 

addition, there is an accelerated schedule for Twinrix®, which previously was included in the 

HepB resolution that has now been added to this resolution for HepA:

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



All children should receive hepatitis A vaccine at 1 year of age (i.e., 12-23 months). 

Vaccination should be completed according to the licensed schedules below. 

Catch up is recommended for all unvaccinated children and adolescents aged 2-18 years. 

Children and adolescents who have not previously received HepA vaccine should be 

vaccinated routinely at any age. 

Vaccine1 Age # of 

Doses

Schedule2

Havrix (pediatric formulation) 1 year 2 doses 0, 6-12 months

Vaqta (pediatric formulation) 1 year 2 doses 0, 6-18 months

Twinrix (adult formulation)3 18 years 3 or 4

doses

• 0, 1, 6 months;

• 0, 7 days, 21-30 days, 12 

months (accelerated 

schedule)

1. Use of brand names is not meant to preclude the use of other hepatitis A vaccines where appropriate. 

2. 0 months represents timing of the initial dose; subsequent numbers represent months after the initial dose. 

3. Only persons 18 years of age are eligible to receive Twinrix through the VFC program. 

The Recommendation for Use of Hepatitis A Vaccine for Post-Exposure Prophylaxis remains 

unchanged:

Healthy persons aged 12 months through 18 years, who have been exposed to HAV 

within the prior 14 days and have not received hepatitis A vaccine previously should 

receive a single dose of hepatitis A vaccine as soon as possible. The hepatitis A 

vaccine series can be completed with the second dose at least 6 months after the first 

dose. 

For the Selected Special Categories section, clarifying language has been added related to the 

use of vaccine and IG that will be part of the HepA recommendation update that ACIP has been 

discussing:





A single dose of hepatitis A vaccine should be administered to infants age 6-11 months 

of age traveling to countries outside the United States for which protection against 

hepatitis A is recommended on CDC’s Traveler’s health website 

(https://wwwnc.cdc.gov/travel/). Infants should then receive the full 2-dose hepatitis A 

vaccine series at ≥12 months of age as recommended. 

Persons administered IG for whom hepatitis A vaccine is also recommended should 

receive a dose of vaccine simultaneously with IG. If only IG or only vaccine is available, 

either available product should be administered as soon as possible. For persons who 

receive vaccine, the second dose should be administered according to the licensed 

schedule to complete the series. The efficacy of IG or vaccine when administered >2 

weeks after exposure has not been established.

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Recommended Intervals/Doses remains unchanged. Pregnancy was previously listed under 

Contraindications and Precautions and has now been removed. There are no changes to the 

Statement Regarding Update Based on Published Documents. 

Motion/Vote: VFC Resolution for Hepatitis A Vaccine 

Dr. Moore made a motion to approve the VFC resolution for hepatitis A vaccines. Dr. Walter

seconded the motion. No COIs were declared. The motion carried with 14 affirmative votes, 0 

negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

Introduction

David S. Stephens, MD

Chair, Meningococcal WG

Advisory Committee on Immunization Practices

Emory University

Dr. Stephens began by thanking ACIP, the WG members, and CDC for his last 4 years of 

service on the Meningococcal WG. He then introduced the Meningococcal Vaccine WG 

session. This session focused on Serogroup B meningococcal (MenB) booster doses in persons

at increased risk for serogroup B meningococcal disease. ACIP recommends a MenB primary 

series for persons at increased risk for serogroup B meningococcal disease. Booster doses are 

not currently recommended for persons who remain at increased risk. During the February 2019 

meeting, data were presented to ACIP on:

 Persistence of the immune response following MenB primary vaccination

 Immunogenicity, safety, and persistence of a MenB booster dose

 GRADE and EtR Framework for MenB booster doses

 WG’s interpretation and policy options for MenB booster doses

In terms of activities subsequent to the February 2019 meeting, the WG has: 1) reviewed ACIP 

feedback received during the February 2019 meeting; 2) discussed potential programmatic 

challenges of MenB booster doses, with specific updates proposed to CDC’s outbreak guidance 

related to booster dose implementation during outbreaks; and 3) developed an updated ACIP 

statement to harmonize existing meningococcal vaccine recommendations and potential MenB 

booster recommendations into a single document.

Meningococcal Vaccines

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The agenda for this session included presentations on the following topics:

 Summary of immunogenicity and safety data, GRADE, EtR, and policy options for MenB 

booster doses in persons at increased risk for serogroup B meningococcal disease

 Updated the ACIP Statement for Meningococcal Vaccination in the US

 Votes on the MenB booster doses for persons at increased risk and on the updated ACIP 

Meningococcal Vaccine Statement

Serogroup B Meningococcal Vaccine Booster Doses

Sarah Mbaeyi, MD, MPH 

CDC Lead, ACIP Meningococcal Vaccines WG

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Mbaeyi sincerely thanked Dr. Stephens for his leadership of this WG over the last couple of 

years, and emphasized that they had enjoyed having him as their Chair. During this session, 

she summarized data evaluated by the WG to inform policy options for serogroup B

meningococcal vaccine booster doses in persons at increased risk for serogroup B 

meningococcal disease. She summarized information previously presented to ACIP at the 

February 2019 meeting. This included reviewing the rationale for MenB booster doses in 

persons at increased risk for serogroup B meningococcal disease; summarizing the WG’s 

interpretation of the persistence of the immune response following a MenB primary series and 

immunogenicity and persistence of a MenB booster dose; summarizing the GRADE and EtR for 

MenB booster doses in persons at increased risk; and reviewing the WG’s considerations for 

policy proposals related to MenB booster doses.

Meningococcal disease is a serious infection that can progress rapidly, and 1 in 10 patients die 

despite antibiotic treatment. Among survivors, 1 in 5 have long-term sequelae. The incidence of 

meningococcal disease continues to decline in the US, with an incidence of 0.11 cases/100,000 

population in 2017. Serogroup B now accounts for approximately 40% of all cases. While 

incidence is low in the US, certain individuals are at increased risk for serogroup B 

meningococcal disease. These include persons with complement deficiency, complement 

inhibitor use, anatomic or functional asplenia, and microbiologists routinely exposed to Neisseria 

meningitidis isolates. The magnitude of increased risk in these individuals can be up to 10,000-

fold. Based on the population estimates for each group, these individuals comprise less than 

0.1% of the US population aged at least 10 years. In addition, persons may be at increased risk 

due to a serogroup B meningococcal disease outbreak. During a college outbreak, the 

magnitude of increased risk is approximately 165-fold, and is even higher in freshmen, oncampus residents, and Greek-life students. Approximately 35,000 college students are at 

increased risk annually due to an outbreak. 

In February 2015, ACIP recommended that persons aged 10 years or older at increased risk for 

serogroup B meningococcal disease receive a MenB primary series. These groups also are 

recommended to receive quadrivalent meningococcal conjugate (MenACWY) vaccination, with 

booster doses every 5 years thereafter for as long as risk remains. In addition, in June 2015, 

ACIP recommended that adolescents aged 16-23 years may be vaccinated with a MenB 

primary series based on individual clinical decision-making, with a preferred age of 16-18 years.

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College students are at increased risk for serogroup B meningococcal disease and outbreaks 

compared to similarly aged young adults who do not attend college1. Thirteen serogroup B 

outbreaks have been reported since 2013. In all of these outbreaks, a MenB primary series was 

implemented as part of outbreak response2. Two of these outbreaks occurred at a New Jersey 

university during a 3-year period. During the first outbreak in 2016, MenB-FHbp vaccination was 

recommended for all undergraduates3. In the most recent outbreak reported in February 2019, 

MenB vaccination was again recommended to all undergraduates. For the first time, booster 

vaccination also was recommended for students who completed a primary series at least 1 year 

previously. Thus, college students are the primary group at increased risk for serogroup B 

outbreaks who may have received a MenB primary series as healthy adolescents. Current 

MenB vaccination coverage among adolescents is low, with approximately 15% of 17 year olds 

receiving at least 1 dose in 2017, though coverage has steadily increased since licensure4,5

[

1Mbaeyi, et al. Pediatrics. 2019; 2Soeters, et al. Congress of the European Meningococcal and 

Haemophilus Society. 2019; 3Soeters, et al. Emerging Infectious Diseases. 2016; 4Walker, et al. 

MMWR. 2018; 5Jones-Jack, presented at the National Immunization Conference (2018)].

Additionally, several serogroup B cases have been reported in patients who received MenB 

vaccination. Of the 5 reported cases to-date who received any MenB vaccine, 3 were fully 

vaccinated with MenB-4C, 1 was partially vaccinated with MenB-4C, and 1 was partially 

vaccinated with MenB-FHbp. Among those fully vaccinated with MenB-4C, 2 had known 

underlying conditions that may have increased their risk for meningococcal disease and 1 was a 

young adult with no known conditions. The interval from last MenB dose to disease onset 

ranged from 5 to 26 months. Preliminary analysis on the strains showed that potential protection 

is dependent on just 1 of the 4 antigens, NHBA, and human serum bactericidal activity (hSBA) 

results suggest that MenB-4C likely confers limited protection against these strains. No isolate 

was available for the patient who was partially vaccinated with MenB-FHbp, and thus the strain 

could not be analyzed further. Information on these patients is not sufficient to evaluate or 

compare effectiveness of MenB vaccine products.

In summary, although incidence of serogroup B meningococcal disease is low in the US, a small 

group of individuals are at substantially elevated risk. ACIP recommended a MenB primary 

series for persons at increased risk over 4 years ago. Evidence presented to ACIP during the 

February 2019 meeting suggests that waning of immunity occurs within 1-2 years following 

primary vaccination and thus, some vaccinated people may no longer be protected. Serogroup 

B outbreaks among college students continue to occur. One university to-date has implemented 

off-label and ACIP recommendations for a booster dose. Finally, no further data on persistence 

following a primary series or booster dose are expected from the manufacturers. Additional data 

on MenB effectiveness and duration of protection in adolescents and adults in US populations 

may take years to generate.

Turning to a review of the WG’s interpretation of the persistence of the immune response 

following a MenB primary series, clinical trial data for both 3-dose and 2-dose MenB-FHbp 

primary series data from baseline (or pre-vaccination) through 48 months post-primary series for 

each of the four test strains showed that antibodies wane by 12 months following completion of

a MenB-FHbp primary series and then remain stable for up to 4 years in healthy adolescents1. 

For MenB-4C, four clinical trials have been conducted to assess immunogenicity and 

persistence to each of the 4 vaccine antigens through 7.5 years post-primary series. 

Persistence following a MenB-4C primary series was difficult to generalize due to the elevated 

baseline titers in two studies, heterogeneous results by vaccine antigens, different time points 

assessed in different studies, and more limited persistence data for NHBA, which contributes 

most to strain coverage in the US2. In light of this, the WG’s interpretation was that antibodies 

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wane by 2 years following the primary series in healthy adolescents and adults, though they 

may wane earlier [1Adapted from Marshall H, Lancet Infectious Diseases 2017 and Vesikari, 

Vaccine 2019; 2Adapted from Read RC, Vaccine 2017; Block SL, Vaccine 2015; Szenborn L, 

Pediatr Infect Dis J. 2018; Perrett KP, Vaccine 2015; Nolan T, Vaccine 2019; Santolaya ME, 

Lancet 2012; Watson PS, Expert Review of Vaccines 2019, and results on clinicaltrials.gov; * 

hSBA titer of 1:5 used in US/Poland study].

In addition, persistence of MenB primary vaccination against diverse serogroup B strains, 

including from college outbreaks, has been assessed in several observational studies. Variable 

patterns of short-term persistence were observed when measured up to 12 months postvaccination1-4. In another recent study to assess seroprevalence at Princeton University 

following the 2013 outbreak, suboptimal short-term immunogenicity followed by substantial 

antibody waning to the outbreak strain was observed in students vaccinated with MenB-4C. At 2 

months post-vaccination, 61% of students had an hSBA titer of ≥1:4, which declined to 24% by 

20 months post-vaccination5 [1Lujan, et al. Clin Vaccine Immunol. 2017; 2Lujan, et al. Clin Infect 

Dis. 2017; 3Giuntini et al, Clin Vaccine Immunol. 2017; 4Basta, et al International Pathogenic 

Neisseria Conference (2018); 5 Basta, et al. Congress of the European Meningococcal and 

Haemophilus Disease Society (2019)]. 

In summary, given the variable rate of waning between vaccine types and between studies, 

antibody persistence following a MenB primary series was difficult to generalize across the two 

vaccine products. It must also be noted that the two vaccines are completely different, and 

evaluations of immunogenicity and persistence were conducted using different strains and 

immunologic endpoints, and thus cannot be directly compared. However, the WG felt that by 1 

to 2 years following a MenB primary series, booster vaccination is indicated for persons who 

remain at increased risk.

Dr. Mbaeyi next reviewed the immunogenicity and persistence of a MenB booster dose. 

Immunogenicity and persistence of a MenB-FHbp booster dose administered 4 years after 

completion of either a 2 or 3 dose primary series demonstrates a robust immune response at 1 

month with gradual waning and evidence of persistence through 26 months post-booster dose.

Thus, the WG’s assessment was that the immune response to a MenB-FHbp booster dose 

persists for at least 2 years in healthy adolescents, and given the gradual antibody decay 

pattern, may last longer [Adapted from Pfizer data presented to ACIP Meningococcal WG].

For MenB-4C, regardless of timing since completion of the primary series (whether 2, 4, or 7.5 

years), a robust immune response was demonstrated 1 month following either a MenB-4C or 

investigational MenABCWY booster dose. No studies assessed persistence of a MenB-4C 

booster dose. However, following a booster dose with the investigational MenABCWY vaccine 

with the same MenB component as MenB-4C, antibody persistence was observed through 12 

months post-booster for most antigens. While there are no data on immune persistence 

following a MenB-4C booster dose to inform the WG interpretation, the WG took into account 

the demonstration of persistence of an investigational MenABCWY booster dose through 12 

months, as well as modelled data presented by the manufacturer during the February 2019 

meeting suggesting that persistence is likely several years [Adapted from Szenborn L, Pediatr 

Infect Dis J. 2018; Nolan T, Vaccine 2019; Watson PS, Expert Review of Vaccines 2019;

* hSBA titer of 1:5 used in US/Poland study]. 

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To summarize, a MenB booster dose elicits a strong immune response, and the persistence 

appears to exceed that of a MenB primary series. Thus, the WG’s interpretation was that 

antibody persistence of a MenB booster dose is likely at least 2-3 years, and may be longer, in 

healthy adolescents and adults.

Dr. Mbaeyi next summarized the GRADE and EtR for MenB booster doses in persons at 

increased risk for serogroup B meningococcal disease. The over-arching policy question was, 

“Should persons vaccinated with a MenB primary series who remain at increased risk for 

serogroup B meningococcal disease receive a MenB booster dose?” The population was 

persons aged 10 years or older at increased risk due to specific underlying conditions and 

microbiologists, and persons exposed during a serogroup B meningococcal disease outbreak.

The intervention was either a MenB-FHbp or MenB-4C booster dose, and the comparison was 

no booster dose. Outcomes of interest related to MenB booster doses were identified by the 

WG, though only data on short-term immunogenicity, persistence of the immune response, and 

SAEs were available. For GRADE, there were four PICO questions, two for each group at 

increased risk and two for each MenB vaccine. Beginning with persons at increased risk due to 

underlying conditions or microbiologists, for both MenB-FHbp and MenB-4C, the evidence type 

across outcomes was a 4, indicating that the overall certainty of evidence in this population is 

very low.

The WG also reviewed additional considerations as part of the EtR Framework. Persons at 

increased risk due to certain underlying medical conditions and microbiologists comprise a small 

group at substantially increased risk. Thus, in this group, prevention of serogroup B 

meningococcal disease is an important concern. However, immunogenicity to MenB-4C is 

reduced in persons with complement deficiency or complement inhibitor use compared to 

healthy controls, and these persons may be at increased risk for meningococcal disease even if 

they develop antibodies following MenB vaccination. Thus, in these persons, the desirable 

effects of vaccination may be more limited compared to others in the target group. The 

undesirable effects of booster vaccination are expected to be minimal. Safety of the MenB 

primary series has been demonstrated in several large evaluations in healthy persons, though 

no data on booster doses (including repeated doses) are available in persons with underlying 

conditions. In a survey, the majority of pediatricians and family physicians stated that they would 

recommend a MenB primary series for children at increased risk, demonstrating acceptance of 

MenB vaccination, though there is a disparity by provider type which may reflect levels of 

awareness or feasibility. There are no data on cost-effectiveness in this population. 

Thus, the WG’s interpretation was that for this population at increased risk, serogroup B 

meningococcal disease is a problem of public health importance. The desirable effects of a 

MenB booster dose may vary in persons with underlying conditions. The undesirable effects are 

likely minimal. The intervention of a MenB booster dose is favored, but there is very low 

certainty of the evidence. The target population may feel uncertain that the desirable effects are 

large relative to undesirable effects, though there is important uncertainty in how much these 

persons value the main outcomes. A MenB booster dose is probably acceptable to key 

stakeholders, though it is uncertain whether the intervention is a reasonable and efficient 

allocation of resources or is feasible to implement. Thus, the majority of WG members were in 

favor of proposing a recommendation for MenB booster doses in this population.

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Next, Dr. Mbaeyi reviewed GRADE and EtR for persons at increased risk due to a serogroup B 

meningococcal disease outbreak. For MenB-FHbp, the evidence type across outcomes was a 4, 

indicating that the overall certainty of evidence is very low. For MenB-4C, the evidence type was 

a 3 or 4 across outcomes depending on study design, indicating that the overall certainty of 

evidence is low.

The WG also reviewed other considerations as part of the EtR Framework for this population. Of 

the serogroup B cases in the US, 7% are outbreak-related and college students are 

disproportionately affected1. Limited data are available on effectiveness and duration of 

protection in adolescents and adults, and no data are available in US populations. Following 

mass vaccination with MenB-4C in a region of Quebec, Canada that is experiencing increased 

rates of disease, the vaccine was estimated to be 79% effective in persons under the age of 20 

years up to 4 years post-vaccination, but the confidence intervals were very wide2. However, an 

additional factor is that the evidence to-date suggests no impact of MenB vaccines on 

meningococcal carriage; thus, herd immunity is unlikely3,4. As the safety of a MenB primary 

series has been demonstrated through multiple evaluations following mass vaccination during 

outbreaks5-8, the harms are likely minimal for a booster dose.

The WG also reviewed factors specific to college outbreaks. All 13 universities that experienced 

outbreaks since MenB vaccines became available implemented a MenB primary series, 

indicating acceptance of MenB vaccines to stakeholders, though first-dose coverage varied 

widely1. This may reflect values, feasibility, or other factors. Additionally, 1 university to-date has 

implemented a booster dose even in the absence of an ACIP recommendation, reflecting 

acceptance of this intervention. MenB mass vaccination during college outbreaks is resourceintensive, though is estimated to be more cost-effective than universal vaccination of all 

students at college entry2,3. Outbreaks require intensive coordination, significant human 

resources, and action among multiple stakeholders to efficiently respond within a short time4-7. 

MenB booster doses may create additional complexities, though colleges have already 

demonstrated the feasibility of conducting mass vaccination under very challenging 

circumstances. Indeed, additional challenges related to booster dose implementation were 

noted at the New Jersey University, including additional communication and logistical 

challenges related in part to the lack of an ACIP recommendation as well as challenges in 

determining booster eligibility (e.g., if a primary series was completed and which product was 

used) [1Soeters, et al. Congress of the European Meningococcal and Haemophilus Society. 

2019; 2Fisher, et al. J Adol Health, 2018; 3Leeds et al., Am J Prev Med, 2018; 4Capitano et al., 

Hum Vacc and Imm, 2018; 5Ritscher et al., J Am Coll Health, 2018; 6Fiorito et al., J Am Coll 

Health, 2017; 7Fisher et al., J Adol Health, 2018].

Thus, the WG’s interpretation was that for this population at risk during an outbreak, serogroup 

B meningococcal disease is a problem of public health importance. The desirable effects of a 

MenB booster dose may be large, with minimal undesirable effects. The intervention of a MenB 

booster dose is favored, but there is very low certainty of the evidence. The target population 

may feel that the desirable effects are large relative to undesirable effects, and there is probably 

variability in how much these persons value the main outcomes. The WG considered that the 

intervention of a MenB booster dose is acceptable to key stakeholders, a reasonable and 

efficient allocation of resources, and feasible to implement. Therefore, the WG favored 

recommending a MenB booster dose for persons at increased risk during a serogroup B 

outbreak.

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To summarize the WG’s deliberations for MenB booster dose policy options in persons at 

increased risk, the WG reviewed the data just presented on the persistence of the immune 

response following a MenB primary series, immunogenicity, persistence, and safety of a MenB 

booster dose, and results from the GRADE and EtR evaluations. The majority of WG members 

agreed upon the need for and timing of MenB booster doses. A small minority felt there was 

insufficient evidence on the safety and efficacy of MenB booster doses to inform policy options.

The following represents the views of the majority of WG members.

The WG felt that MenB booster vaccination is necessary to sustain protection in persons who 

remain at increased risk. The WG suggested that a MenB booster dose is indicated at 1 year 

following completion of the primary series. Greater persistence is expected after the booster 

dose, and thus, a longer interval for repeat booster doses may be considered. Given the serious 

nature of meningococcal disease, the WG felt that the potential benefits of MenB booster 

vaccination outweigh potential risks in this population. As with MenB primary vaccination, 

challenges in the implementation of MenB booster doses are anticipated, but the WG felt the 

potential benefits of booster vaccination justify the additional implementation efforts that will be 

needed. Thus, the WG proposed that ACIP recommend MenB booster vaccination in persons 

aged 10 years or older at increased risk for serogroup B meningococcal disease who previously 

completed a MenB primary series. This recommendation does not apply to persons who 

previously completed a MenB primary series as an adolescent based on individual clinical 

decision-making and who are not at increased risk for serogroup B meningococcal disease. For 

persons with complement deficiency, complement inhibitor use, asplenia or microbiologists, a 

MenB booster dose is recommended 1 year following completion of a MenB primary series, 

followed by booster doses every 2-3 years thereafter, for as long as increased risk remains. For 

persons determined by public health officials to be at increased risk during an outbreak, a onetime MenB booster dose is recommended if it has been ≥1 year since completion of a MenB 

primary series. A booster dose interval of ≥6 months may be considered by public health 

officials depending on the specific outbreak, vaccination strategy, and projected duration of 

elevated risk.

Dr. Mbaeyi concluded that ACIP would be asked to vote on the policy proposal for MenB 

booster doses in persons at increased risk for serogroup B meningococcal disease. In advance 

of the afternoon’s vote, ACIP members were asked to provide any additional feedback on the 

WG’s policy proposal for MenB booster doses. She indicated that Vote #1 for this meeting

would be for ACIP to recommend MenB booster vaccination in persons aged ≥10 years at 

increased risk for serogroup B meningococcal disease who previously completed a MenB 

primary series.

Discussion Points

Dr. Atmar requested a reminder about the basis for the original recommendation approval in 

terms of MenB vaccines and whether it was based on safety and immunogenicity. He also 

wondered about the rationale for not conducting a formal cost analysis, though he understood 

the cost-effectiveness assessment done for the original recommendation and what the extra 

cost and benefit would be for a booster recommendation

Dr. Mbaeyi indicated that immunogenicity data were reviewed for both vaccines when making 

the recommendation for persons at increased risk, as well as for adolescents who are not at 

increased risk. They do not have any VE or duration of protection estimates that informed that 

policy. The WG did not conduct a formal cost-effectiveness evaluation because these 

recommendations are for a very small group of individuals at increased risk. They are not 

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considering booster recommendations for adolescents who are not at increased risk, which is a 

much broader population. They attempted to look at some of this, but found that there was a 

wide variety in the assumptions that would have to be made and the NNV based on the 

uncertainty around the level of increased risk, population size, et cetera. The numbers were not 

very meaningful, which was why she did not present them.

Dr. Cohn requested a reminder of the total estimated size of the population for both increased 

risk and the average number of college students who are vaccinated during an outbreak.

Dr. Mbaeyi replied that the population at risk would be a little under 300,000 and the college 

students would be about 35,000. These are estimates. For example, the majority of people with 

complement component deficiency are not aware of their deficiency. Often people find out after 

their first episode of meningococcal disease or another infection, or if they have family members 

with the deficiency.

Dr. Maldonado (AAP) pointed out that since this is a booster recommendation and pediatricians 

are somewhat concerned about how to counsel families given the very low risk of disease, she 

suggested stating actual numbers of cases in addition to incidence and prevalence. For 

example, there is a total of 134 cases of MenB disease in all ages in the US based on the 2017 

surveillance data from CDC.

To respond to Dr. Atmar’s question, Dr. Stephens indicated that the license of MenB vaccine is 

based on immunogenicity and the correlate of protection is the serum bactericidal assay (SBA). 

That has been a standard for a number of years for most meningococcal vaccines. In terms of 

the complement inhibitor, even though they are recommending vaccination and booster 

vaccination in this group, this problem has not been solved in terms of the seriousness and data 

have been presented on this in the past. As pointed out, this is a small group for whom boosters 

are being recommended at this time.

Dr. Hunter wondered whether the ACHA, NACCHO, and ASTHO liaisons could comment on the 

issue that if there is an outbreak on a college campus how much the booster recommendation 

would help in the implementation of a response to that in terms of vaccine history.

Dr. Even (ACHA) responded that in an outbreak situation, students are unlikely to know whether 

they have received MenB previously. This depends upon the recordkeeping and ease of 

recordkeeping. If all students’ immunization records are quickly available in an electronic record, 

that is beneficial. However, that is not a general practice. Her assumption is that a campus 

would use the vaccine that was most readily available and administer that as widely as possible. 

In a situation in which a student was aware of the vaccines they had before, every attempt 

would be made to use that same vaccine. The speed of the response seems to be more 

important in an outbreak situation.

Dr. Zahn (NACCHO) replied that it depends upon the size of the target population. If 30 people 

potentially could be exposed, this is very different from the potential for 3000 people to be 

exposed. Either way, there is a potential for missing people. Even if there is no 

recommendation, extra doses are still going to be given because some people who have been 

vaccinated may not realize it. It is known that after a couple of years, immunity wanes. To him, it 

is an obvious question and concern and there is potential utility to it. There is an issue in terms 

of getting everyone’s vaccine status right and over-vaccinating. There is a better chance that 

someone might know what they had in the previous 6 months. On balance, he thought the 

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recommendation would be helpful, clarified the question, and would be welcomed by public 

health. 

Dr. Messonnier expressed appreciation for the systematic way the WG worked through the 

issue and the desire to fill a gap in the recommendations, which she thought tried to provide 

helpful guidance to clinicians. The groups at risk have a more lifetime risk. While she 

understood the limitations of the available data and the desire to provide recommendations 

beyond a single booster, she wondered whether the WG could comment separately on 

reassurance that they did not have concerns about safety, recognizing that the effectiveness of 

repeat vaccination is not known after even a first booster.

Dr. Stephens said that the WG reviewed the data from a safety standpoint and did not have a 

major concern with regard to the safety of repeated booster doses. This is a memory-inducing 

vaccine. Therefore, a booster dose should provide significantly longer protection than the 

original priming series. There are no data to support that, but that is the message from the 

limited data that are available.

Dr. Atmar pointed out that if this recommendation were to go forward, it would be important for 

those at lifetime risk to generate those data because it may well be that the interval could be 

longer as more doses have been delivered.

Dr. Ezeanolue expressed concern about the foundation upon which they would make a 

recommendation that people with sickle cell disease risk should be immunized with the primary 

series and receive a booster dose every 2 to 3 years for life.

Dr. Stephens replied that it is known that this vaccine works and does prevent disease in high 

risk groups. In those individuals with functional asplenia, the risk is significant. Prophylactic 

penicillin is used with some individuals for other increased risk for lengthy periods of time. Thus, 

his response was that he would believe that a booster could help protect these individuals. The 

question regarded how often the booster should be given and how long the recommendation 

should continue for this particular group. He agreed with Dr. Atmar that more data are needed 

on repeated boosters.

Dr. Mbaeyi added that a major reason persons with sickle cell disease are considered a risk 

group for meningococcal disease in general is that if they do get it, they have an extremely high 

case fatality rate. Approximately 60% to 70% of people can get an overwhelming postsplenectomy infection. Therefore, it is important to consider them in this population.

Dr. Ezeanolue stressed that while he understood why this needed to be done, he was 

wondering how they were going to explain that this recommendation is being made with limited 

available data. He suggested that ACIP should commit to collecting these data in the future and 

reviewing the information again in 5 years.

Dr. Quach (NACI) thought it would be interesting to look at this vaccination strategy as an added 

value above and beyond chemoprophylaxis. There have been thoughts about giving prophylaxis 

to people on eculizumab, because the meningococcal disease was non-vaccine type. She 

wondered how much more would be added by boosting with MenB. As a microbiologist, it was 

not clear to her whether she would want the vaccine every 2 to 3 years. The study was from 

2005 but the process in the laboratory is now safer working with Biosafety Level 2 (BSL-2) and 

above such that the risk may no longer be the same. She found the recommendation to be very 

heavy in terms of boosting.

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Dr. Mbaeyi said that the WG tried to better understand these issues and they recognized that 

every 2 to 3 years is a pretty short interval. The WG presented every 5 years as an option to 

ACIP, but ACIP had concerns that the data did not support this interval. She agreed that there 

are gaps in the data. They do not have more refined estimates among microbiologists since that 

2005 paper. As Dr. Stephens mentioned, there are still a lot of issues to be worked out with 

people taking complement inhibitors and how much vaccination actually protects them. 

However, the WG felt that they know that they are at exceptionally high risk and there is a 

possibility of benefit in these groups, so they should continue recommending a primary series 

and booster doses in this group.

Dr. Messonnier pointed out that there is a routine review of recommendations every 5 years. 

ACIP is certainly welcomed to include language in their statement directing CDC to try to find 

ways to evaluate this. It would be difficult to have a standalone study, so they would be looking 

for existing studies among these groups in which blood is being drawn from patients with sickle 

cell, for example. CDC will look for collaborators who have clinical care of these patient 

populations to determine whether there is a way to answer some of the questions. Perhaps 

someone in the larger community knows of a researcher who is working on sickle cell disease 

who could connect CDC with someone to help answer these questions.

Dr. Bernstein said that since the two vaccines are not interchangeable, he struggled with calling 

it a “booster” in the population of students during an outbreak for whom vaccine status and 

product type may not be known. It was not clear whether they would be doing these individuals 

a service by giving them a single dose of vaccine since one of the two products is a 0, 1 month 

schedule. Perhaps the recommendation should be extended for those who have not received 

MenB vaccine in college or for whom vaccination status and product are unknown.

Dr. Mbaeyi indicated that the WG discussed this in-depth and it is a major feasibility concern. 

The ACIP recommendation would be to use the same product and that the vaccine products are 

not interchangeable, just as it is for the primary series. The WG recognizes that this is a 

challenge during an outbreak, and CDC attempted to review with the WG potential guidance for 

CDC’s outbreak guidance document, understanding that they are not always going to get it right 

but do feel that these students should be offered the chance to get a booster vaccination. The 

New Jersey University presented to the WG about their experience. While it sounded like it was 

a challenge, they felt overall that it was something they could work with.

Dr. Hunter’s perception was that the booster recommendation would offer more flexibility rather 

than limiting the direction of an outbreak response. At least if it was determined later that 

someone was vaccinated a second time, it would not be against the recommendation.

Dr. Fryhofer (AMA) said that as a practicing physician, she has had difficulty figuring out which 

other vaccines her patients have received. It is not indicated on the Georgia Registry of 

Immunization Transactions and Services (GRITS). Oftentimes, she has to call a pharmacy or 

pediatrician, which can be quite cumbersome. It is important to include the specifics on 

registries and in notes.

Dr. Even (ACHA) added that with the general lack of a broad recommendation for all entering 

college students to receive the MenB vaccine and having it be a clinical decision-making 

recommendation, uptake is low. Colleges would understand that they have some students who 

have previous doses, but would be looking at it as an initial outbreak dose such that the booster 

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might be the flexibility for those who already had vaccine at some point in the past, but that this 

is the outbreak dose they are under recommendation to give.

Dr. Stephens made a motion to approve the language reading, “ACIP recommends MenB 

booster vaccination in persons aged ≥10 years at increased risk for serogroup B meningococcal 

disease who previously completed a MenB primary series.” 

Dr. Lee indicated that she had a counter motion. She recognized that there still was a great deal 

of uncertainty, but acknowledged that they still had to make a decision in the face of that 

uncertainty. She strongly felt that there should be the equivalent of a post-marketing 

requirement specific to this area, because additional safety and effectiveness are needed, 

including with the interchange of the different products if that happens in outbreak settings. The 

counter motion would be to, “Consider shared clinical decision-making for populations who 

remain at increased risk, which is a heterogeneous population” because of Dr. Quach’s 

comments about whether a blanket recommendation was being made in the face of uncertainty 

versus a recommendation that would allow people to use their judgment. While there were 

some populations for which she felt more strongly about it, there were others where she felt that 

it was less clear what the right answer would be and they were mixing them all together.

Dr. Ezeanolue agreed that while they did not have all of the data needed, they had enough data

to make a recommendation if it also committed to collecting additional data. Attached to that is 

that there are 100,000 people with sickle cell, for example. He clarified that he supported Dr. 

Stephens’ motion with this amendment to collect additional data.

Dr. Romero noted that with two motions on the table, they should go with Dr. Stephens’ motion 

as Chair of the WG. Dr. Ezeanolue’s supported Dr. Stephens’ motion with the amendment 

regarding data and seconded the motion to move forward.

Dr. Messonnier pointed out that recommendations usually do not have the language that Dr. 

Ezeanolue suggested as part of the paragraph. That could be included regardless of the 

recommendation language.

Dr. Atmar requested that a counter proposal reflecting Dr. Lee’s recommendation be drawn up 

during lunch so that in the event that the first motion by Drs. Stephens and Ezeanolue was 

voted down, they could review it before voting. Dr. Romero confirmed that this could be done.

Dr. Talbot pointed out that this recommendation did not state when or how often to do this after 

the primary series.

Dr. Cohn clarified from a procedural perspective that Dr. Ezeanolue had put an amendment on 

the table. Technically, if that amendment was seconded, they would have to vote on the 

amendment and then vote after the public comment on the proposed amendment. She thought 

Dr. Messonnier’s comment that this language could be incorporated but not included in the 

policy would be an option as well.

Dr. Romero requested further clarification from Dr. Messonnier.

Dr. Messonnier clarified that they have worked hard, especially in the last 5 years, to make the 

recommendations clearly pertain just to vaccination and not other language. Many years ago, 

the recommendation language was so complicated, people felt that it was difficult to understand. 

The language Dr. Ezeanolue suggested could be part of the paragraph leading up to the actual 

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recommendation and it could be in the statement rather than actually be included in the 

language ACIP votes on.

An inquiry was posed regarding whether the shared decision-making would be just for persons 

at increased risk for meningococcal disease. There are concerns about shared decision-making 

in an outbreak setting, given how challenging this would be for those who deal with outbreaks.

Dr. Moore supported the original recommendation in that the reason a routine recommendation 

is important for boosters for individuals at increased risk is that there is no question that they 

need boosting in order to be protected against MenB disease. There is no question that if they 

wish to be protected and they are at increased risk, they need to be boosted. The best evidence 

available suggests that this should be done 2 to 3 years later. It is important to collect ongoing 

information to understand whether this needs to be done lifelong or if the timeframe can be 

lengthened. This needs to be a clear guidance that if someone is in one of these increased risk 

categories, it is a recommendation versus a requirement. People choose all of the time not to 

get vaccines that are recommended for them, but for protection, they need the booster.

Dr. Lee clarified that she was not talking about outbreaks. She was talking about the at risk 

population.

Dr. Stephens commented that shared decision-making would be very difficult in this setting 

where there are obvious risks. Interpretation potentially could be different among people at risk 

for whom ongoing risk is not necessarily going to change. To be soft in terms of this 

recommendation would be a mistake.

Dr. Ezeanolue wanted to put on record that he did not believe shared decision-making would 

help guide what they do. If they were going to make this recommendation based on recognizing 

the limitations of the data, they should make a recommendation that would help them collect the 

data that would guide them in further review.

Dr. Fryhofer (AMA) said that speaking as a practicing physician, they must think about who is 

giving these vaccines (private offices, public health, et cetera). They do not have the expertise 

that ACIP does. When ACIP makes a recommendation, it is not a law. Shared decision-making 

does occur with the patient and the person offering and providing the immunization. Specific 

guidance is needed, and she thought that the shared decision-making was somewhat of a 

copout.

Dr. Hunter said that he was not against the shared decision-making possibility for the high risk 

groups, but the initial recommendation for vaccinating the high risk groups is a routine 

recommendation. He requested confirmation that if they recommended shared decision-making 

for the booster, that would be routine for the initial series and shared decision-making for the 

booster.

Dr. Lee withdrew her motion, but requested clarification. The reason she was thinking about this 

was because if it became a recommendation, it might become a requirement for microbiologists 

to receive the vaccine and if they opt out, there could be a potential consequence. In thinking 

about Dr. Quash’s comment about whether risk has changed for microbiologists, what an isolate 

is may be unknown when it is received. Therefore, enhanced protection might make sense. In a 

known setting, this would be different. Specific to the asplenia population and the balance of 

prophylaxis and vaccination, prophylaxis would not be stopped in those patients with ongoing 

asplenia for multiple reasons, some of which could be sickle cell, but could be due to a variety of 

reasons. She just wanted to ensure that they think of the ongoing safety and benefit/risk 

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balance for that population. She had no challenge at all for people on eculizumab who are at 

extremely high risk for MenB or meningococcal disease in general or the other groups at 

increased risk.

Dr. Romero pointed out that the scenario Dr. Lee described of an unknown isolate coming in 

occurred at their hospital recently.

Dr. Stephens said he thought the Sejvar study conducted in 2005 probably needed to be 

updated. Some cultures are still done without the type of protection needed, so the unknowns 

are of concern. To all of the points, more data are needed to further assess risk.

Dr. Messonnier added that the Sejvar study was conducted during a time when meningococcal 

rates were higher and they were able to demonstrate an increased risk. The absolute risk now is 

so much lower that it will be much more difficult to identify whether there is still substantive risk 

associated with laboratory exposures. The problem is that it is an occupational health hazard. It 

would be difficult unless there are concrete data showing that they are not at risk to remove the 

recommendation because of exactly these types of incidents such as the tragic incident at 

Emory University that was preventable because there was a vaccine.

Dr. Maldonado (AAP) said that her understanding was that the MenB vaccine is a shared 

decision-making vaccine, not a routine vaccine.

Dr. Romero said that was correct, but they were talking about high risk individuals.

Dr. Cohn added that there is a routine recommendation for persons who are at increased risk.

Dr. Maldonado (AAP) said she requested clarity because she has received many emails from 

AAP members who are concerned, because they wondered whether this meant they had to 

start vaccinating everyone because they might be at risk. She stressed that they need to make it 

really clear that the vaccine itself is not routinely recommended, but that a booster would be 

routinely recommended for people who already have been vaccinated.

Dr. Kimberlin (AAP) requested clarity regarding whether Vote #1 included college students.

Dr. Mbaeyi clarified that Vote #1 was only for people who are identified as being at increased 

risk for meningococcal disease.

Dr. Maldonado (AAP) pointed out that the table talks about outbreaks, which is college students.

Dr. Messonnier said she thought the language that was put up for a proposed vote may have 

been simplified too much. She suggested that over lunch, they revise the wording. She asked 

the CDC leads to write language that included as background the information Dr. Ezeanolue

requested that clearly would be part of what they would be saying, so that they could see that as 

well as the recommendation language.

Dr. Romero pointed out that they would need to make new motions upon returning from the 

lunch break since the wording would be revised during that time. He asked whether Drs. 

Stephens and Ezeanolue would be willing to withdraw their motions and reconsider them after 

the lunch break.

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Dr. Stephens withdrew his motion and Dr. Ezeanolue withdrew his second with an amendment.

During the lunch break, Vote #1 was amended to read as follows:

For persons aged ≥10 years with complement deficiency, complement inhibitor use, asplenia, or 

microbiologists:

 ACIP recommends a MenB booster dose 1 year following completion of a MenB primary 

series followed by MenB booster doses every 2-3 years thereafter, for as long as 

increased risk remains.

For persons aged ≥10 years determined by public health officials to be at increased risk during 

an outbreak:





ACIP recommends a one-time booster dose if it has been ≥1 year since completion of a 

MenB primary series.

A booster dose interval of ≥6 months may be considered by public health officials 

depending on the specific outbreak, vaccination strategy, and projected duration of 

elevated risk.

The following additional guidance will be included based on the feedback received:







These recommendations do not apply to persons who previously completed a MenB 

primary series as an adolescent based on individual clinical decision-making and who 

are not at increased risk for serogroup B meningococcal disease.

MenB vaccines are not interchangeable. The same product must be used for all doses.

Collection of safety and effectiveness data for repeated booster doses of MenB vaccine 

in persons at increased risk for serogroup B meningococcal disease is needed for the 

ongoing evaluation of these recommendations by the ACIP.

Dr. Stephens made a motion to approve Vote #1 as amended. Dr. Lee seconded the motion.

Updated ACIP Statement for Meningococcal Vaccination in the US

Sarah Mbaeyi, MD, MPH 

CDC Lead, ACIP Meningococcal Vaccines WG

National Center for Immunization & Respiratory Diseases

Centers for Disease Control and Prevention

Dr. Mbaeyi reviewed the updated ACIP statement for meningococcal vaccination in the US. In 

terms of background, the last statement was published in 2013 and included ACIP 

recommendations for MenACWY vaccination. Since that time, 5 Policy Notes related to 

MenACWY and recently-licensed MenB vaccines have been published. In 2019, an updated 

statement was developed to consolidate all existing ACIP recommendations for MenACWY and 

MenB vaccines in a single document. In addition, if ACIP voted during this meeting to 

recommend MenB booster doses in persons at increased risk, these recommendations would 

be included in the document. The objectives of the updated statement are to: 1) describe the 

background on meningococcal disease, epidemiology, and risk groups; 2) provide updated 

information on currently licensed and available vaccines; 3) describe the process undertaken 

and rationale used in support of ACIP recommendations; and 4) provide ACIP 

recommendations and guidance for use of meningococcal vaccines.

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A systemic review of the literature was conducted related to safety, immunogenicity, and 

effectiveness of MenACWY and MenB vaccines in the age groups in whom the vaccines are 

licensed. Existing MenACWY and MenB recommendations were consolidated and clarified, and 

preliminary MenB booster recommendations were drafted. The draft statement was shared with 

WG group members and ACIP voting members to provide an opportunity for feedback prior to 

this meeting.

Information was included on the 4 vaccines that are currently licensed and available in the US, 2 

MenACWY and 2 MenB vaccines. Additionally, two vaccine products included in the previous 

ACIP statement are no longer available in the US, polysaccharide meningococcal vaccine and a 

combined Hib and meningococcal serogroups C and Y vaccine. Thus, detailed information and 

recommendations related to these two vaccines were not included in the updated statement.

All recommendations for the currently licensed MenACWY and MenB vaccines were included, 

starting from MenACWY introduction in 2005 through preliminary MenB booster dose 

recommendations in 2019 as shown on this table:

Key changes in the updated statement include a compilation of all existing MenACWY and 

MenB recommendations, as well as the proposed new recommendation for MenB booster 

doses, in a single document. The previous “Category B” language for MenB primary vaccination 

in adolescents will be updated to, “ACIP recommends a MenB primary series for individuals 

aged 16-23 years based on shared clinical decision-making.” In addition, the appendices with 

guidance for chemoprophylaxis of close contacts and management of outbreaks are no longer 

part of the ACIP statement. Guidance for these aspects of public health management are 

included in CDC guidance documents.

Dr. Mbaeyi indicated that Vote #2 for this meeting would be to affirm the updated statement 

titled, “Meningococcal Vaccination: Recommendations of the Advisory Committee on 

Immunization Practices.” 

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Discussion Points

Dr. Stephens made a motion to affirm the updated statement “Meningococcal Vaccination: 

Recommendations of the Advisory Committee on Immunization Practices.” Dr. Frey seconded 

the motion. There was no further discussion.

Motion/Vote #1: Meningococcal Vaccine Booster Doses

Dr. Stephens made a motion to approve the following language pertaining to booster doses of 

meningococcal vaccines:

For persons aged ≥10 years with complement deficiency, complement inhibitor use, asplenia, or 

microbiologists:

 ACIP recommends a MenB booster dose 1 year following completion of a MenB primary 

series followed by MenB booster doses every 2-3 years thereafter, for as long as increased 

risk remains.

For persons aged ≥10 years determined by public health officials to be at increased risk during 

an outbreak:

 ACIP recommends a one-time booster dose if it has been ≥1 year since completion of a 

MenB primary series.

 A booster dose interval of ≥6 months may be considered by public health officials depending 

on the specific outbreak, vaccination strategy, and projected duration of elevated risk.

The following additional guidance will be included based on the feedback received:

 These recommendations do not apply to persons who previously completed a MenB primary 

series as an adolescent based on individual clinical decision-making and who are not at 

increased risk for serogroup B meningococcal disease.

 MenB vaccines are not interchangeable. The same product must be used for all doses.

 Collection of safety and effectiveness data for repeated booster doses of MenB vaccine in 

persons at increased risk for serogroup B meningococcal disease is needed for the ongoing 

evaluation of these recommendations by the ACIP.

Dr. Lee seconded the motion. No COIs were declared. The motion carried with 14 affirmative 

votes, 0 negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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Discussion Points

Dr. Atmar said he was somewhat bothered by a booster recommendation with the limited 

information available. However, based on the rationale for the initial approval and the risk 

groups being at definite risk, he was persuaded by the earlier discussion to vote for approval.

Dr. Hunter said that he was reassured that there will be follow-up by CDC.

Motion/Vote #2: Meningococcal Statement 

Dr. Stephens made a motion to affirm the updated statement “Meningococcal Vaccination: 

Recommendations of the Advisory Committee on Immunization Practices.” Dr. Frey seconded 

the motion. No COIs were declared. The motion carried with 14 affirmative votes, 0 negative 

votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

VFC Resolution Updates: Meningococcal Vaccines

Frank Whitlatch

Immunization Services Division

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Mr. Whitlatch indicated that the purpose of this resolution was to update the resolution to reflect 

(a) currently available meningococcal conjugate vaccines; and (b) new recommendations for 

booster doses for serogroup B meningococcal vaccines. In addition, the language regarding the 

intervals for one of the serogroup B vaccines covered by the resolution has been updated to 

more closely reflect the current ACIP recommendation language. Yellow highlighting in the 

presentation is used to indicate changes to the resolution in comparison to the prior approved 

version.

The only change to the Meningococcal Conjugate Vaccines (MenACWY) section will be removal 

of reference to HibMenCY since the vaccine is no longer available in the VFC program. There 

are no changes to the Recommended Vaccination Schedule and Intervals, Recommended 

Dosages, or Contraindications and Precautions components of this section.

For the Serogroup B Meningococcal Vaccines (MenB) section, there are no changes to Eligible 

Groups. The Recommended Vaccination Schedule and Intervals table has a column added for 

the booster dose for Serogroup B meningococcal vaccine and the second table note has been 

updated to more closely reflect the current ACIP recommendation language:

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Vaccine (1) Age 

Group

Dosing Schedule 

(Primary Series)

Dosing Schedule (Booster Dose)

MenB-4C (Bexsero, 

GSK)

10–18 

years

Two doses, at least one 

month apart (0 and ≥1 

month schedule)

For children at increased risk due to 

complement deficiency, complement 

inhibitor use, or functional or anatomic 

asplenia: 

A booster dose is recommended if it has 

been at least one year since primary series; 

repeat every 2-3 years as long as risk 

remains.

 

For children at increased risk due to a 

serogroup B outbreak:

Booster dose recommended if it has been 

at least one year since primary series. If 

recommended by public health officials, 

booster dose may be given if it has been at 

least 6 months since primary series. 

 

Booster doses are not recommended for 

adolescents who are not at increased risk 

for meningococcal disease.

MenB-FHbp 

(Trumenba, Pfizer)

10–18 

years

Persons at increased 

risk for meningococcal 

disease including during 

serogroup B outbreaks: 

Three doses (0, 1-2, and 

6 month schedule)

 

Adolescents who are not 

at increased risk for 

meningococcal disease: 

Two doses (0, 6 months) 

(2)

1. Use of brand names is not meant to preclude the use of other comparable US licensed vaccines. 

2. If the second dose is administered earlier than 6 months after the first dose, a third dose should 

be administered at least 4 months after the second dose. 

Recommended Intervals/Doses, Contraindications and Precautions, and the Statement 

Regarding Update Based on Published Documents remain unchanged for serogroup B 

meningococcal vaccine.

Motion/Vote: VFC Resolution for Meningococcal Vaccines 

Dr. Stephens made a motion to approve the VFC resolution for meningococcal vaccines. Dr. 

Ault seconded the motion. No COIs were declared. The motion carried with 14 affirmative votes, 

0 negative votes, and 0 abstentions. The disposition of the vote was as follows:

14 Favored: Atmar, Ault, Bernstein, Ezeanolue, Frey, Hunter, Lee, McNally, Moore, 

Romero, Stephens, Szilagyi, Talbot, Walter

 0 Opposed: N/A

 0 Abstained: N/A

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Introduction

Robert Atmar, MD

Chair, Dengue Vaccines WG 

Advisory Committee on Immunization Practices

Dr. Atmar reminded everyone that the new Dengue Virus WG was convened in October 2018 in 

response to the Sanofi resubmission of the BLA to the FDA for DENGVAXIA®. There were 

previous dengue vaccine discussions in 2016-2017 as part of the ACIP Flavivirus Vaccines WG, 

with ACIP presentations on dengue and dengue vaccines in February and June 2017. Dengue 

vaccine discussions were put on hold in early 2018 while Sanofi Pasteur reanalyzed long-term 

vaccine trial data and reworked the BLA. There was an FDA Vaccine and Related Blood 

Products Advisory Committee (VRBPAC) review in March 2019 and the vaccine received

approval in May 2019. 

Regarding the Dengue Virus Vaccine WG’s terms of reference, the objective of the WG is to 

develop recommendations for the use of safe and effective dengue vaccines in the US and US 

Territories among children and adults, including those living in dengue-endemic areas and for 

persons traveling from non-endemic to endemic areas. The WG’s goals with regard to dengue 

vaccines are to:

 Review safety, immunogenicity, and efficacy data from clinical trials and long-term follow-up 

studies for dengue vaccines submitted for licensure in the US

 Develop evidence-based recommendations for implementation of vaccination in the public 

and private sectors with dengue vaccines licensed for US use

 Identify areas where additional data are needed (i.e., future directions) to improve control of 

dengue through safe and cost-effective vaccination

Dr. Atmar indicated that presentations would be provided on the following topics during this 

session: 

 Dengue Epidemiology in the US 

 DENGVAXIA® Phase III Clinical Trials and Long-Term Follow-Up

 Dengue Vaccines WG Considerations and Next Steps

Future WG plans are to present a GRADE analysis and preliminary DENGVAXIA® 

recommendations during the October 2019 ACIP meeting, and present final recommendations 

for a vote during the February 2020 ACIP meeting.

Dengue Virus Vaccine

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Epidemiology of Dengue

Gabriela Paz-Bailey, MD, PhD, MSc

Dengue Branch 

National Center for Emerging and Zoonotic Infectious Diseases

Centers for Disease Control and Prevention

Dr. Paz-Bailey presented on the global epidemiology of dengue, considerations pertaining to

dengue testing as the vaccine requires pre-vaccination serostatus screening, and dengue 

epidemiology in the US and its territories to consider where a dengue vaccine may be 

beneficial.

Regarding the global dengue burden of disease and where it is a public health problem, dengue 

is the most important virus transmitted by mosquitoes worldwide. Dengue virus (DENV) is 

transmitted by Aedes species mosquitoes, primarily by Aedes Aegypti and Aedes Albopictus. It 

is arguably the most important arbovirus in terms of worldwide morbidity and mortality with an 

estimated 390 million infections; approximately 100 million of which are associated with clinical 

manifestations; 500,000 hospitalizations; and 20,000 deaths estimated in 2010. Epidemics 

typically have a cyclical pattern over years and with seasonal incidence correlated with higher 

temperatures and rainfall months. Dengue virus is a public health problem throughout the 

tropics and subtropics in 128 countries and is endemic in Asia and Latin America including the 

Caribbean, Africa, and the Pacific. With increasing travel and connectivity and rising world 

temperatures, more areas are becoming at risk [S Bhatt et al. Nature 000, 1-4 (2013) 

doi:10.1038/nature12060].

Infections can occur with any of four distinct dengue virus serotypes. Natural infection results in 

lifelong protection for that serotype. In theory, a person can be infected with dengue 4 times in 

her or his lifetime. About 25% to 35% of infections are symptomatic. Typical classic symptoms 

include abrupt onset of fever, headache, retro-orbital pain, muscle and bone pain (hence the 

term “breakbone” fever), and often rash. Of those who are symptomatic, between 10% to 20% 

are hospitalized and 1% to 5% of clinical cases result in severe dengue. Hospitalization rates 

vary regionally based on early recognition, appropriate management, and local clinical practices

[Flasche et al, Plos Med 2016; 13(11):e1002181; Wilder-Smith A. et al, Lancet 2019;393:350-

63; Salje H. et al, Nature 2018; 557:719-728]. 

The detection of all virus serotypes has expanded worldwide together with growing 

hyperendemicity, which means that more than one serotype is circulating. Diagnostic capability 

has changed over time. Until the 1980s, the majority of areas had reported only 1 or 2 dengue 

virus serotypes. More recently, all 4 virus serotypes frequently co-circulate.

1 An example of this 

is Puerto Rico, which has monitored serotype distribution for over three decades. In addition to 

co-circulation of multiple virus serotypes, the proportion of each of the 4 serotypes circulating 

varies over time, with 1 or 2 serotypes predominating in any given year2 [

1Messina JP et al. 

Trends in Microbiology 2014:22;3:138-146; 2Arbonet, National Arbovirus Surveillance System].

This graph emphasizes that dengue transmission is dynamic, constantly changes, and 

seroprevalence measured 10 years ago does not necessarily reflect seroprevalence today. This 

data comes from a cohort study in a particular Managua district in Nicaragua. The data show

how seroprevalence by age group changed substantially between 2004 and 2015. The y-axis 

shows the proportion seropositive and the x axis shows age. Highlighting the difference 

between the yellow line that is 2004 and the dark blue line that is 2015, 50% of children were 

seropositive by age 4.5 in 2004, but 50% seroprevalence was reached by age 11 years in 2015: 

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Of the $8.9 billion estimated global financial burden of dengue, most ($5.1 billion) results from 

patients who are hospitalized or die from dengue. Age, co-morbidities, host genetics, and virus 

strain are risk factors for severe dengue. Heterotypic secondary infections is the greatest risk

factor for dengue hemorrhagic fever and dengue shock syndrome [Shepard DS et al. Lancet ID 

2016; 18(8):935-41; Wilder-Smith A. et al, Lancet 2019;393:350-63]. 

The way in which secondary dengue infections increase the risk of severe dengue is thought to 

be explained by the phenomenon of antibody-dependent enhancement (ADE). The mechanism 

is that at a specific concentration, heterotypic antibodies bind but do not neutralize virions of the 

subsequent infecting dengue type, leading to higher viremias and non-structural antigenemia 

and imbalanced inflammatory responses that result in vascular leak and severe dengue disease

or shock. Only recently has it been demonstrated that mid-range specific dengue antibody titers 

are associated with risk of severe dengue disease. Data from a longitudinal analyses of the risk 

or hazard of severe dengue disease by pre-existing DENV-Ab titer for the pediatric dengue 

cohort in Nicaragua illustrated that dengue hemorrhagic fever and dengue shock syndrome 

showed a cumulative hazard of 11% for intermediate antibody titer compared to 1.6% among 

dengue naïve children and 1.5% for children with high titers. That is, having no antibody titers or 

having high antibody titers is better than just having some antibody titers [Leah C. Katzelnick et 

al. Science 2017;358:929-932].

Thus, there is a question about what percentage of primary, secondary, or post-secondary 

infections result in hospitalizations and severe disease. Sam Clifford and Stefan Flasche of the 

London School of Hygiene kindly shared modeling results fit to the most recent DENGVAXIA®

Phase III trial data to present during this meeting. The data show what proportion of first and 

second infections progresses to the given disease outcome (symptomatic VCD, hospitalization, 

and severe dengue) in a follow up period of 2 years for symptomatic VCD and 5 years for 

hospitalization and severe dengue. The model estimates that 19% (14.8-23.2) of primary 

infections result in symptomatic dengue, 3% (1.9, 4.4) are hospitalized, and less than half a 

percent (0, 0.7) progress to severe dengue. The uncertainty is clear based on the confidence 

intervals for each of these estimates. The estimate for secondary infections is that 35% (31.4-

38.7) result in symptomatic dengue, 11% (9.4, 11.8) in hospitalizations, and 2% (1.8, 2.9) in 

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severe disease. This shows that the majority but not all hospitalizations occur after secondary 

infections in this model [Sam Clifford and Stefan Flasche LSHTM, personal communication; 

Sridhar, NEJM 2018;379:327-40, Flasche et al, Plos Med 2016; 13(11):e1002181].

The current dengue vaccine requires screening for dengue serostatus before vaccination. Likely 

IgG testing will be used to determine previous serostatus. No IgG test is currently FDAapproved in the US, and there are limited data regarding cross-reactivity with other flaviviruses 

after the Zika epidemic. When thinking about test performance, sensitivity and specificity are not 

the only target metrics for assay development. Tests with a given sensitivity and specificity are 

more likely to misclassify truly seronegative individuals in low transmission settings than in high 

transmission settings, because the pretest probabilities of testing positive are lower. In an

example of a 20% seroprevalence, with a test specificity of 90% and sensitivity of 70%, 36% of 

persons testing positive would be false-positives or actually negative for past dengue infection.

In a higher prevalence setting of 80% seroprevalence, the positive predictive value (PPV) is 

higher at 97% and only 3% of persons testing positive would be false positives. The problem 

here would be imperfect sensitivity, since more than half of those testing negative would be true 

seropositive who could benefit from the vaccine.

Turning to a review of dengue epidemiology in the US and its territories in consideration of 

which areas may benefit from a dengue vaccine, economist and modelers in collaboration with 

WHO have proposed levels of risk based on seroprevalence to identify areas that would benefit 

from vaccination and where the risk of false negatives would be low. Areas with 10% 

seroprevalence at the target age group to start vaccination are considered very low risk, 30% 

low risk, 50% moderate risk, 70% high risk and 90% very high risk [Flasche et al, Plos Med 

2016; 13(11):e1002181].

Ideally, it would be beneficial to have seroprevalence data available to assess risk. But as for 

the rest of the world, limited seroprevalence data are available in the US and its territories. A 

proposal has been made to use the dengue risk definition in the CDC Yellow Book that provides 

health information advice for travelers. Since dengue epidemics in many regions typically occur 

every 3 to 5 years, the Yellow Book assumes that endemic areas would be the most likely to 

report more than 10 dengue cases in at least 3 distinct years over the most recent 10-year 

period. These areas are classified as frequent/continuous risk. For areas that did not meet the 

frequent/continuous definition, the Yellow Book classifies areas with at least some or sporadic

risk defined as any area with at least one reported, locally acquired case in the previous 10 

years. Areas with no reports of DENV transmission were classified as no evidence of risk.

These criteria then define endemic areas as including the US territories of American Samoa, 

Puerto Rico, US Virgin Islands, and the US-affiliated Federated States of Micronesia and Palau.

In terms of the US territories that would fall into frequent continuous risk and the epidemiology 

of dengue in Puerto Rico, data comparing dengue incidence rates in Puerto Rico to countries in 

Latin America show that rates are similar to several countries. For Brazil, rates are 10 times 

higher than for all other countries, and the scale is different. It is important to note that reporting 

practices and under-reporting vary by country [Source: Talia Quandelacy and Mike Johansson, 

personal communication; Data from dengue passive surveillance from Ministries of Health and 

latest population census]. 

Regarding suspected cases for the most recent years in Puerto Rico, passive surveillance data 

show that the highest number of cases occurred in 2010 and 2013. In 2013, there was a large 

Chikungunya virus (CHIKV) outbreak, and in 2016 a large Zika virus (ZIKV) outbreak. There has 

been some, but little, circulation of dengue since 2014.

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This map shows the number of cases by Puerto Rico municipality. Dengue transmission occurs 

through the island, but with local heterogeneity. Areas with higher population density have more 

cases, such as San Juan in the Northeast and Ponce on the South Coast: 

For each of the territories, Dr. Paz-Bailey presented the number of cases and rates for the most 

recent years when there was transmission. Passive surveillance data from Puerto Rico for 

2010-2013 show that the highest numbers and rates of confirmed and probable cases are in the 

10-14 age group and the 15-19 years of age group. Hospitalized cases and severe illness cases 

are also highest in these age groups. The number of cases in older age groups drops likely 

because most people have probably had 2 infections by age 20. However, almost 50% of cases 

occurred among adults. A high degree of under-reporting has been documented in Puerto Rico. 

A recent published study estimated that for every 1 reported case, there are about 100 cases 

not reported. For every hospitalized case reported, there are 5 to 9 cases not reported [Arbonet, 

National Arbovirus Surveillance System].

With regard to dengue-associated deaths, the case fatality rate has varied by outbreak year. 

Data on fatal dengue cases by age in Puerto Rico (n=64) from 2010–2013 show that in contrast 

to the higher number of cases in children and adolescents, only 6 of the 64 laboratory-confirmed 

deaths in this period were in children and only 1 was in the 15 to 19 year old age group. Death 

occurred in adults 20 to 88 years of age. Thus, 90% of lab positive deaths were in adults from 

2010 through 2013 [Arbonet, National Arbovirus Surveillance System].

One of the few seroprevalence surveys available for Puerto Rico was done in 2007 in Patillas in 

the Southeast of the island. The seroprevalence among 10-11 year olds was 43%, and by 16-18

years of age, 60% were seropositive [Argüello DF et al. Incidence of dengue virus infection in 

school-aged children in Puerto Rico: a prospective seroepidemiologic study. Am J Trop Med 

Hyg. 2015 Mar;92(3):486-91. doi: 10.4269/ajtmh.14-0231. Epub 2015 Feb 2]. 

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With regard to how dengue test results are processed in Puerto Rico, persons who are 

symptomatic and seek care will visit their private provider’s office or go to an emergency 

department (ED). If the provider suspects dengue, a dengue test is ordered. Testing is 

centralized at the Public Health Laboratory, where polymerase chain reaction (PCR) and 

immunoglobulin M (IgM) tests are done. These results are sent back to the name in the form 

that appears as the provider, which could be the clinical laboratory, hospital, or physician that 

ordered the test. It is not clear how many of these make it back to the patient’s record, but 

anecdotally it is reported that many do not. Dengue is a notifiable disease and all results are 

kept in the Arbovirus Surveillance System that is managed by the Puerto Rico Department of 

Health (PRDH). 

There is an immunization registry in Puerto Rico. There are 220 providers for the VFC Program 

that cover about 60% of the vaccines administered. There are also 300 private providers, 

including vaccination centers. Those provide about 40% of the vaccines that are administered in 

Puerto Rico. The immunization registry covers both children and adults and it is pretty complete. 

They have 70% coverage of private providers and 100% of providers in VFC [Personal 

communication, Angel Rivera and Iris Cardona, PRDH].

The past 25 years have seen several periods of increased dengue virus transmission in the US 

Virgin Islands, with the most recent in 2012-2013. During the last outbreak, a seroincidence 

study was conducted in schools in St. Croix in 2012. Of the school-aged children and 

adolescent, 20% were recently infected with dengue virus and 17% of teachers were recently 

infected. In 2012 and 2013, 310 cases were reported. In terms of the age distribution and 

incidence rate, the highest number and rate were in the 10-14 year age group, while 69% of 

reported cases were in adults [Arbonet, National Arbovirus Surveillance System, CDC. MMWR 

2013;62 (9): 171-172]. 

The US Pacific territories and affiliated independent states include American Samoa, Guam, the 

Northern Mariana Islands, Palau, the Marshall Islands, and the Federated States of Micronesia. 

Periodic dengue outbreaks have been detected among the Pacific Islands since 1958, usually 

with only one dengue serotype at a time1. Whether continuous endemic transmission occurs in 

any of the islands is unclear. However, a 2010 serosurvey in American Samoa among adults 

found that 96% percent of the sampled population had dengue IgG antibody2. In 2016-2018, 

there was a large dengue outbreak in American Samoa with over 1000 laboratory-confirmed

cases3. Data from passive surveillance show that the highest numbers and rates of cases and 

hospitalizations are among 10-14 and 15-19 year olds in American Samoa in 2017-20184

[

1Hammon et al., Am J Trop Med Hyg, 1958; 2Lau, EID, 2013; 3Cotter et al. MMWR 

2018:67(47);1319–13222; 4Arbonet, National Arbovirus Surveillance System].

In terms of sporadic and uncertain transmission, there have been large dengue outbreaks 

historically in Hawaii. More recently in 2015-2016, there were 264 cases reported due to DENV 

1 on the big island of Hawaii. The outbreak strain was a DENV 1, that was different from the 

2001 Hawaii outbreak strain. A serosurvey in a small rural community in 2001 on the island of 

Maui showed that 14% had evidence of recent infection and 17% had evidence of past 

infection1 [1Hayes JM et al. TRSTMH 2006; 100 (6):559-566].

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Several counties in Southern and Central Florida have reported locally acquired cases. In 2009 

and 2010, nearly 90 cases were reported. In 2013, a locally acquired dengue outbreak took 

place and 21 cases were reported. A survey in Martin County showed that 2% had evidence of 

recent infection, while a separate survey in Key West showed that 4% has evidence of a recent 

infection and 7% had evidence of past infection [Moody-Geissler S et al. CSTE 2014; 

Messenger AM et al. VBZD 2012;14(11):783-787].

Since 1980, Texas has detected a number of outbreaks with a few locally acquired dengue 

cases in border cities that are associated with large outbreaks in neighboring Mexico cities. In 

2013, there were 24 locally-acquired cases reported1. A serosurvey conducted in 2005 at the 

end of a DENV 2 outbreak showed large differences in seropositivity on the Mexico side of the 

border compared to the US side. Overall, IgM positivity measuring recent infections was 32% in 

Matamoros, Mexico and only 4% in Brownsville, Cameron County on the US side. IgG

seroprevalence was high in Matamoros at 77% for all age groups and 39% overall in Cameron 

County in the US side2 [1Arbonet, National Arbovirus Surveillance System; 2Ramos et al Am J 

Trop Med Hyg 2008;78(3):364-369].

About 800 dengue cases a year are reported among US travelers on average. The most 

common travel destination overall has been the Caribbean, but this varies year to year. About 

800 dengue cases a year are reported among US travelers. ACIP’s Dengue Vaccines WG will 

likely review available data for foreign-born or territory-born travelers and consider that data in 

making any dengue vaccine recommendations [Arbonet, National Arbovirus Surveillance 

System].

In summary, dengue is a public health problem throughout the tropics and subtropics including 

the Americas. Unfortunately, seroprevalence data are limited. Seroprevalence affects assay 

performance. US territories with frequent or continuous risk include Puerto Rico, US Virgin 

Islands, American Samoa, and some US-affiliated Pacific Islands. Cases and incidence rates in 

Puerto Rico, US Virgin Islands, and American Samoa are highest in the 10-19 age group, but 

many cases occur in adults as well. 

Discussion Points

Dr. Romero asked what the average turnaround time is for the test in Puerto Rico once it 

reaches the center. He also wondered how much disruption had occurred in the Puerto Rico 

immunization registry due to the recent climate challenges they have faced, and whether they is 

an estimate of when it will be back to its previous state.

Dr. Paz-Bailey indicated that the average turnaround time depends upon the volume of testing 

that is occurring, but it is about 2 weeks. While the vaccine immunization registry probably was 

disrupted in the immediate days after Hurricane Maria, CDC has learned through conversations 

with the health department that it is now fully operational.

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DENGVAXIA® Phase III Clinical Trials and Long-Term Follow-Up

Gustavo Dayan, MD

Global Clinical Sciences

Sanofi Pasteur

Dr. Dayan discussed Sanofi Pasteur’s Phase III clinical trials for DENGVAXIA® in terms of 

efficacy, safety, and long-term follow-up. DENGVAXIA® which is a tetravalent live-attenuated 

viral vaccine. The development of this vaccine has taken more than 20 years of research. 

DENGVAXIA® combines two different viruses, YF 17D virus where the capsid and non-structural 

proteins act as the backbone of the vaccine and also the dengue viruses. The precursor 

membrane and envelope genes were isolated from each of the 4 dengue serotypes and were 

inserted into that backbone. The result was a chimeric vaccine, which is a combination of the 2 

viruses that produces protection against the 4 dengue serotypes.

The DENGVAXIA® development program began in 2002. It comprises 26 clinical studies that 

have been completed that involved 41,000 subjects enrolled in 16 countries. Over 28,000 

subjects received DENGVAXIA® in clinical trials and most of them (N=21,000) were 9 to 45 

years of age. DENGVAXIA® is now licensed in 20 countries, including the US and the EU. The 

indication in the US is for seropositive individuals 9 to 16 years of age.

Regarding the efficacy results, the program included two Phase III clinical trials, both of which 

were randomized, observer-blind, placebo-controlled studies. Study CYD14 was conducted in 

children 2-14 years of age in 11 centers across 5 countries in Asia Pacific (Malaysia, 

Philippines, Thailand, Vietnam, Indonesia). Study CYD14 enrolled 10,275 children who were 

randomized 2:1 to receive either DENGVAXIA® (N=6841) or placebo (N=3424). Study CYD15 

was conducted in children and adolescents 9-16 years of age in 22 centers across Latin 

America in 4 countries (Brazil, Colombia, Honduras, Mexico) and the US territory of Puerto 

Rico. Study CYD15 enrolled 20,869 children and adolescents who were randomized 2:1 to 

DENGVAXIA® (N=13,920) or placebo (N=6949). Each study also included baseline samples in 

a subset of 2000 subjects for immunogenicity and reactogenicity, in accordance with the WHOrecommendations for the development of dengue vaccines.

Both studies were identical in design. They included 3 doses separated by 6 months each (0,6, 

12 months) and a long-term follow-up period of 5 years after the last injection. The study was 

divided into two phases, the Active Phase and the Hospital Phase. The Active Phase began 

with the first injection and ended at Month 25. The main purpose of this phase was to assess 

efficacy. There was an active surveillance system to be able to detect any suspected dengue 

cases. Efficacy was assessed 1 month after the third injection, which was the primary endpoint 

of the study, and also from the moment of the first injection until Month 25. The studies also had 

a Hospital Phase that began at Month 25 and finished at the end of the studies. In this phase, 

the surveillance system was detecting only hospitalized cases and the primary purpose was 

long-term safety follow-up. In summary, safety for hospitalized and severe dengue was started 

from the beginning of the studies and was continued until the end of both studies.

Regarding the results, both studies met their primary endpoints. Efficacy was approximately 

55% (46.8, 61.7) in CDY14 and approximately 65% (58.7, 69.9) CYD15. They also were able to 

show efficacy against hospitalized dengue and in severe dengue cases. During the long-term 

follow-up, the investigators began to see an increased risk of hospitalized dengue in 

approximately Year 3 in Study CYD14, which was the study conducted in the younger children.

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The protocols included some pre-specified analyses by International Conference on 

Harmonisation (ICH) age groups, and they were able to see that this was particularly focused in 

children 2 to 5 years of age. This safety signal detection prompted the investigators to conduct 

some additional analyses using different age groups. They were able to show that the relative 

risk for hospitalization and severe dengue was lower in subjects who were more than 9 years of 

age, which prompted them to used 9 years of age as the cutoff for the initial indication in 

endemic countries. However, they knew that the age was closely related to the baseline studies 

of prior dengue infection. The problem was that they did not have baseline specimens from all of 

the subjects, because these were collected only in a subset of patients. By design of the 

studies, they had 1 sample in almost all subjects in Month 13. That was 1 month after the third 

injection. Then they faced another problem. They had the blood samples, but not the assay. The 

assay they used was a plaque reduction neutralization test (PRNT) assay, which cannot 

distinguish vaccination from prior infection. It was specifically designed to assess the response 

to the vaccine. Therefore, they had to leverage the NS1 antibody assay to infer baseline 

serostatus from the Month 13 samples. 

In terms of the results of the NS1 Supplemental Analysis, a very different response was seen in 

those who were seropositive in which all of the estimates were to the left of the null value 

indicating protection compared to the seronegative subjects where the estimates were to the 

right of the null value indicating an increased risk. Regarding risk reduction against hospitalized 

dengue in seropositives by serotype among children and adolescent 9 to 16 years of age, the 

US indication, the risk was decreased for all 4 serotypes. Importantly, the upper bound of the 

95% confidence intervals spared the null value.

They also looked at the time to dengue hospitalization in seropositive subject 9 to 6 years of 

age. Looking at the cumulative cases for DENGVAXIA® and the control group, there was a clear 

separation of both curves from the moment of the first injection until the end of the surveillance 

period. They performed a similar exercise for the severe dengue cases among seropositive 

subjects 9 to 16 years of age. The pattern was the same, with separation of the curves for the 

DENGVAXIA® and control group from the first dose until the end of the surveillance period.

Traditional VE was assessed against any symptomatic dengue disease in seropositive subjects 

9 to 16 years of age during the Active Phase. Efficacy was consistent in both studies at 

approximately 75% in Study CYD14 and 76% in Study CYD15. They also assessed the efficacy 

among seropositive subjects 9 to 16 years of age by serotype. There was efficacy for each of 

the 4 types and the lower bound of the confidence interval was spared the null value.

The investigators also assessed the population level effects, for which they looked at the 

attributable risk and cumulative incidence over a 5-year period. Basically, they looked at the 

differences in the attributable risk, which is the difference in the incidence in vaccinated and 

non-vaccinated children. They observed that the attributable risk for hospitalized dengue cases 

was -15% and severe dengue was -4%.

In summary of the efficacy data, the investigators observed a different profile by serostatus that 

was favorable for seropositive subjects and unfavorable for seronegative subjects. In 

seropositive subjects 9 to 16 years of age, there was protection against symptomatic, 

hospitalized, and severe dengue. The evidence of vaccine efficacy was consistent across both 

Phase III clinical trials and there was protection against the 4 serotypes. In terms of population 

effects, vaccination of 1000 seropositive subjects would prevent 15 hospitalized cases and 4 

severe dengue cases in the conditions of these clinical trials.

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Regarding the overall safety profile after any injection in the DENGVAXIA® and saline placebo 

control group in Study CYD15, the percentages in the reactogenicity subset were somewhat 

higher in the vaccine compared to the placebo. This was particularly true for the injection site 

reactions. In terms of the safety analysis set, SAEs were similar in the vaccine compared to the 

control group at ≤ 28 days post any dose and >28 days to 6 months post any dose. The 

investigators also assessed viscerotropic and neurotropic disease because this vaccine has the 

backbone of the YF vaccine virus, so there was a concern that vaccination with DENGVAXIA®

could cause viscerotropic or neurotropic disease. However, no cases were identified. No 

vaccine-related deaths occurred during the study.

In terms of the solicited systemic reactions that were assessed in both trials (pain, erythema, 

swelling), the percentage of pain and swelling were somewhat higher in subjects receiving the 

vaccine compared to those receiving placebo in Study CYD15. Most of the injection site 

reactions were Grade 1 or Grade 2, short in duration, and began within 3 days after vaccination. 

Solicited systemic reactions (fever, headache, malaise, myalgia, asthenia) also were assessed. 

The percentages were fairly similar between the vaccine and placebo recipients, with no 

clinically significant differences. Most reactions were mild or moderate in intensity and of short 

duration. Unsolicited AEs and ARs also were similar between the vaccine and placebo 

recipients, most were mild or moderate.

There are also post-marketing data because the vaccine has been used. Approximately 3 

million doses have been distributed primarily in Brazil (300,000 doses) and the Philippines 

(830,000 doses) where vaccination campaigns were organized. There were approximately 3000 

spontaneous case reports, including 553 serious AEs. The most frequently reported AEs were 

consistent with the clinical development program. Though some allergic and anaphylactic 

reactions were detected in the post-licensure experience that had not been detected in the prelicensure process, these were rare with a reporting frequency of <0.01%. Approximately 134 

potential allergic reactions occurred in the first 7 days following vaccine and 69 occurred within 

24 hours, and there were 3 cases of anaphylactic reactions. Allergic and anaphylactic reactions

have been included in the prescribing information. 

To summarize the safety results, rates of some solicited reactions were higher in the

DENGVAXIA® versus the placebo recipients. There were low rates of Grade 3 events overall, 

with the majority of reactions being mild to moderate in intensity and transient. Rates of SAEs

among DENGVAXIA® recipients were low and were similar to the control group, and no cluster 

of events was identified. There were no viscerotropic or neurotropic cases and no related 

deaths were reported. Allergic and anaphylactic reactions were detected in post-marketing 

surveillance. 

Regarding the indication and dosing summary, DENGVAXIA® was approved for use in the US 

to prevent dengue disease caused by dengue virus serotypes 1, 2, 3, and 4 in individuals 9 

through 16 years of age with evidence of laboratory-confirmed previous dengue infection and

also living in endemic areas. Previous dengue infection can be assessed through medical 

record of a previous laboratory-confirmed infection or current serotesting prior to vaccination. 

DENGVAXIA® is administered subcutaneously on a 3-dose schedule at 0, 6, and 12 months.

Given that the vaccine is linked to serotesting, Sanofi Pasteur started to explore different 

possibilities to execute serotesting globally and particularly in Puerto Rico. There are two CLIAapproved tests available in Puerto Rico, which are the SciMedx Dengue IgG Serum Microwell 

ELISA and the Biocan RDT - Tell Me Fast Dengue IgG/IgM. The specificity of these tests is very 

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high at 100% for SciMedx and 99.1% for Biocan. This is very important in terms of avoiding the 

possibility of obtaining false positive results.

In conclusion, through multiple studies among more than 25,000 subjects, DENGVAXIA® has 

demonstrated that in seropositive individuals 9 through 16 years of age, the safety profile is 

favorable and there is efficacy against symptomatic, hospitalized, and severe dengue against 

each of the 4 dengue serotypes. 

Discussion Points

Dr. Moore noted that Dr. Dayan mentioned the rates of viscerotropic and neurotropic disease in 

reference to the clinical trials, but she wondered whether this was assessed in the postmarketing surveillance as well.

Dr. Dayan indicated that viscerotropic and neurotropic disease were assessed in both the 

clinical trials and post-licensure experience, with none identified. There was a specific protocol 

to assess this in the clinical trial because it was considered to be an AE of special interest.

Dr. Ezeanolue requested further information about deaths since everyone was tested for 

seropositivity before vaccination, as well as the cost for testing.

Dr. Dayan clarified that when the vaccine was used in the field campaigns, everybody was 

vaccinated because they did not have the information about seropositivity yet. Therefore, 

vaccine use started without the restriction on the seropositive subjects. Once they learned this 

information, they began to incorporate the new recommendation in seropositive subjects. This 

recommendation was incorporated into the FDA submission, and was part of the approval for 

use in the US. He did not know the exact cost of the testing, but did not think it was very 

expensive.

Dr. Maldonado (AAP) said that there is a table with the available tests and costs for them. 

Regarding the earlier studies of DENGVAXIA®, the WHO website still has data from 2017 and 

they have not updated it. There is no citation for those data, so she assumed it was not 

published. However, their pooled data efficacy was much different. Their efficacy against 

serotype 3 was 71.6%, serotype 4 was 76.9%, serotypes 1 was 54.7%, and serotype 2 was 

43.0%. Regarding use of the vaccine in the Philippines, she noted that Dr. Dayan did not 

mention the 14 deaths that supposedly were associated with the vaccine and whether those 

data were ever confirmed.

Dr. Dayan explained that those data combined studies but did not take into account 

seropositivity or serostatus at baseline. The Sanofi Pasteur NS1 Supplemental Study analysis 

was published last year in the New England Journal of Medicine (NEJM) by serostatus. 

Regarding the 14 deaths in the Philippines, the vaccine was approved for use in the Philippines 

in 2015. They followed the WHO recommendations and the recommendations of their own 

regulatory agencies. They conducted various vaccination campaigns with approximately 

800,000 subjects. It took some time for Sanofi Pasteur to make information public because they 

had to develop the assay and produce the analysis. The license was suspended for a while, and 

then it was withdrawn completely. The issue was that the Philippines reported some deaths that 

they said were associated with the vaccine. But it was very difficult to get a clear association 

with the vaccine, and most of the deaths were not biologically confirmed dengue. They reported 

the cases but did not have virologic confirmation sometimes. There are not sufficient data to 

assess the cases completely.

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Dr. Maldonado indicated that she worked with the Philippine Pediatric Society (PPS) on this 

issue, and they had a huge antivaccine response because of this. Whether it is true or not, each 

of the children had a code number and were being followed by the government. These children 

clearly received vaccine or placebo. When she talked to the Ministry of Health and WHO, they 

all had different stories about how they were investigating the deaths. She wondered how 

Sanofi Pasteur handled this.

Dr. Dayan responded that these children received the vaccine, because they were vaccinated 

during the campaign. The problem was to identify whether the deaths were or were not related 

to the vaccine. A special WHO Advisory Committee on Safety looked into the cases, but could 

not draw a finite conclusion. Of course, any death is a problem and Sanofi Pasteur feels very 

sad about that. 

Dr. Maldonado emphasized that he did not mention them at all during his presentation. She 

apologized for belaboring this, but 14 deaths is a big deal. Those children received the vaccine 

and he could have calculated a comparison with children who did not receive the vaccine.

Dr. Messonnier said she thought Dr. Maldonado was recommending that the ACIP WG review 

those original data.

Dr. Maldonado indicated that there are two good papers and additional information about what 

happened can be found on the WHO website.

Dr. Stephens asked whether Dr. Dayan could provide the immunological thinking about why this 

vaccine is protective in those who have had prior disease versus the younger group.

Dr. Dayan indicated that secondary infections are related to more severe disease. This is based 

on different theories, but is not entirely clear. It is thought to be due mainly to ADE. There is an 

increase of antibody titers after the first infection that are protective to that serotype. There also 

is cross-reactive protection against other serotypes, but in short duration. When the heterotypic 

response starts to decrease, the risk of more severe disease increases through different 

mechanisms that triggers an immune response that produces plasma leakage. This is the 

immunological pathogenesis. It is thought that when the vaccine is given to seronegative 

subjects, they are being infected for the first time and creating a primary infection. Therefore, 

they will be at risk of more severe disease when they have a secondary infection. For a person 

who has been infected previously, vaccination would be a secondary infection and would 

decrease the risk of hospitalization and induce efficacy to protect against future infections.

Dr. Cohn inquired as to what number of the approximately 25,000 children in the pooled data 

were from Puerto Rico versus other countries and how generalizable these data actually would 

be to children living in Puerto Rico.

Dr. Dayan indicated that approximately 1300 subjects were recruited in Puerto Rico. There were 

two sites, one in San Juan and one in the Southern part of the island in Guayama. The 

demographic characteristics were fairly similar. The efficacy of the vaccine was about 94%. The 

confidence intervals were wide because there were not many cases, but it is very comparable. 

There were not enough hospitalized cases to assess.

Dr. Messonnier requested confirmation that while the vaccine is licensed in other countries, no 

country is currently routinely using it and that no country has implemented vaccination 

specifically the way that the FDA recommended it for use in the US. Therefore, ACIP would 

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have to make its recommendations based on the available data as no additional data will be 

forthcoming.

Dr. Dayan indicated that different countries had different indications. In the beginning, there was 

an indication for the entire population. When Sanofi Pasteur realized that there was a safety 

signal and the problem with those who were seronegative, they informed all of the regulatory 

authorities and they began to update their recommendations. Most of the updated 

recommendations included the clause of having seropositivity to be eligible for vaccination. The 

vaccine is now available in the private market where the vaccine is recommended. At this point, 

there are no ongoing vaccination campaigns. If the vaccination indication has been updated in a 

country, they have to follow the new indication.

It sounded to Dr. Hunter that ACIP would be asked to vote on a scenario such as 

operationalization in Puerto Rico, with a test that’s sensitivity produces false negatives and false 

positives with a turnaround time of two weeks, and which has never been done anywhere else. 

He did not find this very reassuring as a voting member and thought it would be more 

reassuring to have additional evidence before ACIP votes on this.

Dr. Dayan said that at this point, they were trying to discuss what would be the potential ways to 

use the vaccine in a setting such as Puerto Rico. They have been in discussions with the ACIP 

WG and the regulatory authorities in Puerto Rico to determine how this could be implemented 

because they have some laboratory testing that could be used with the system that Dr. PazBailey explained. Sanofi Pasteur acknowledges that this is difficult to implement. They also have 

some materials, HCP guidelines, and an online training program that potentially could be used 

by HCP, because they want this to be very clear to the HCP who would be administering the 

vaccine. The plan is to make the new information available to everyone as soon as possible. 

They are analyzing additional data from the NS1 analysis.

Dr. Atmar pointed out that the WG already had begun to struggle with this key issue and would 

continue to assess it over the coming months. The WG will present to the full committee the 

results of its struggle with this question. Ultimately, he thought it would strongly influence the 

assessments that ACIP has on the potential utility of the vaccine.

Dr. Hunter pointed out that he was coming at this from the perspective of working at a local or 

state health department where the CDC cannot help them unless invited to do so. If Puerto 

Ricans in some fashion were strongly demanding this and were willing to take the risks because 

they felt that it would benefit them, that would change his opinion.

Dr. Romero emphasized the importance of the voting members airing their questions now, 

because this will be very difficult. 

Dr. Ezeanolue requested clarification regarding whether administering the vaccine to a 

seronegative individual would place them at increased risk for infection or at increased risk for 

side effects.

Dr. Dayan said that Sanofi Pasteur asserts that when seronegative subjects receive the 

vaccine, they have an increased risk of hospitalization and to have more severe disease. 

“Severe disease” was classified by an Independent Data Monitoring Committee (IDMC) as 

increased risk of hospitalization and severe dengue.

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Dr. Ezeanolue emphasized that he would consider increased risk of hospitalization to be a side 

effect, and that if a seronegative person gets the disease after having the vaccination, it would 

be more severe.

Dr. Dayan indicated that VE also was not good for those who were seronegative. For example, 

VE was about 38% to 39% among seronegative subjects who were more than 9 years of age. 

However, the confidence intervals were very wide. VE in those less than 9 years of age was 

lower and the vaccine was not very efficacious in that particular group of seronegatives. On top 

of that, there was increased risk of severe disease.

Dr. Moore requested further information about the allergic reactions that were observed in the 

post-marketing surveillance.

Dr. Dayan replied that the reaction were typically associated with associated with the 

standardized MedDRA query that they used to group all of the reactions. While he did not have 

the complete list, he recalled that they were related to rash, skin reactions, et cetera. They have 

a protocol to follow these subjects. These were considered potential allergic reactions, but none 

of them were anaphylactic reactions. This was done during the pre-clinical and clinical studies, 

and also was detected in the post-marketing experience. The anaphylactic reactions did not 

occur in the clinical studies, but were observed during the post-marketing experience. That is 

why they were included in the indication.

Dr. Ault asked whether VAERS is friendly to Spanish-speakers.

Dr. Shimabukuro indicated that the website, guidance, instructions, and 1-800 number for 

reporting are available in Spanish. The report form itself is in English for multiple reasons, such 

as difficulties with MedDRA coding. There are plenty of opportunities to take a report from 

someone who speaks Spanish as their first language.

Dengue Virus Vaccines

Steve Waterman, MD, MPH

Chief, Dengue Branch 

Centers for Disease Control and Prevention 

San Juan, Puerto Rico

Dr. Waterman summarized the Dengue Vaccines WG’s considerations to date and next steps

for ACIP toward making a recommendation regarding DENGVAXIA®. The FDA approved

indication recommended by the VRBPAC and announced in May 2019 for DENGVAXIA® is for 

children 9-16 years of age who have a laboratory-confirmed previous dengue infection and live 

in an endemic area such as the US territories of American Samoa, Guam, Puerto Rico, and the 

US Virgin Islands.

The Dengue Vaccines WG drafted the following policy question to guide the EtR Framework 

and the GRADE assessment, “Should 3-doses of CYD-TDV be administered routinely to 

persons 9-16 years of age with laboratory-confirmed previous dengue infection and living in 

endemic areas to prevent virologically-confirmed dengue, hospitalizations, and severe dengue?” 

As reported by Dr. Paz Bailey, dengue viruses have caused steadily increasing morbidity and 

mortality worldwide over the last 60 years. In the US territories of Puerto Rico, the US Virgin 

Islands, and American Samoa, dengue viruses circulate at endemic or virtually endemic levels, 

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a situation that also applies to two US-affiliated Pacific nations, Palau and the Federated States 

of Micronesia. Age-specific seroprevalence data are scarce in most of the world, including the 

US. Higher population prevalence of dengue antibody reduces the likelihood of false positive 

pre-vaccination screening tests. Based on modeling of DENGVAXIA® impact with Sanofi trial 

data, the WHO SAGE recommends that countries could consider vaccinating without screening 

at seroprevalence levels in 9 year olds of at least 80%.

Severe dengue can occur in infants, children, and adults. In the Sanofi trials, severe dengue

occurred in about 4% of unvaccinated children with virologically confirmed clinical dengue 

overall. Severe dengue often manifests as a leaky capillary syndrome, which can lead to shock 

and death if untreated. Shock from dengue almost always can be successfully managed if 

monitored for and treated appropriately with fluid replacement. Severe illness can sometimes 

manifest with GI hemorrhage, liver failure, or meningoencephalitis. Higher risk of leaky capillary 

syndrome is associated with secondary dengue infections. The proposed pathogenetic 

mechanism is known as antibody dependent enhancement or ADE. Prospective studies in 

Nicaraguan children have demonstrated higher risk of this syndrome when heterotypic or crossreactive dengue antibody levels fall to moderate levels, consistent with the ADE mechanism.

As Dr. Dayan summarized with regard to the long-term Phase III trial data for DENGVAXIA®, in 

seropositive children 9-16 years, the vaccine is about 75% efficacious against virologicallyconfirmed symptomatic dengue with higher levels of protection for hospitalization and severe 

illness. The vaccine is effective against all four serotypes in seropositives. The highest efficacy 

is for the dengue 4 virus serotype. Depletion antibody studies by Dr. DeSilva at the University of 

North Carolina showed that DENGVAXIA® produces high levels of homotypic antibody for 

dengue 4 compared to the other serotypes. 

However, in seronegatives the risk of hospitalization is higher in vaccinated children with a 

hazard ratio of 1.41 and a hazard ratio for severe disease of 2.44. Apart from this risk in 

seronegatives, the clinical trial safety profile data are comparable in vaccinees and controls. 

The WG’s view is that the quality of these clinical trials is that they are first-rate and the efficacy 

analyses were conducted to the highest standards. As mentioned by Dr. Atmar earlier, the 

Dengue Vaccines WG convened last October after over a year’s hiatus in dengue vaccinerelated discussions as part of the Flavivirus WG. The topics covered during WG meetings over 

the last 8 months have included the following:

 CYD-TDV Phase III trials including long-term follow-up and imputed pre-vaccination 

serostatus analysis

 Epidemiology of endemic dengue in the US

 Published dengue vaccine cost-effectiveness studies

 Clinical dengue and disease severity 

 Review of the EtR and GRADE frameworks 

 Dengue diagnostics and available IgG screening tests and target product profile, with 3 WG 

meetings on IgG tests that might be used for pre-vaccination screening.

 CYD-TDV safety and pharmacovigilance

Dr. Robert Luo presented to the WG on a systematic review of 10 published evaluations of 4 

rapid diagnostic tests. These tests are not FDA cleared tests, but are available in various parts 

of the world and could be performed in the US under Clinical Laboratory Improvement 

Amendments (CLIA) regulations. The sensitivities ranged between 30% and 60%. The 

specificities ranged between 65% and 100%, with wide confidence intervals. The CDC Dengue 

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Branch also conducted a preliminary landscape analysis of over 30 rapid diagnostic tests 

(RDTs) and IgG enzyme-linked immunosorbent assay (ELISA) tests. Both the Luo paper for 

WHO and the CDC assessment point out that these tests were designed for detecting acute 

infection, not past infection. The composition of the panels to evaluate these tests does not 

have information on infections with other flaviviruses or flavivirus vaccinations. Such samples 

are needed to evaluate cross-reactivity and specificity. Sanofi has identified 3 tests, 2 RDTs and 

1 IgG ELISA, that are available in Puerto Rico and American Samoa. One of the RDTs was 

included in the Luo study. Sanofi evaluated the sensitivity and specificity of these tests with a 

well-characterized set of 400 samples including YF and JE neutralization test-positives. This 

evaluation found specificities of >99% for all three tests. When the 3 tests were evaluated with 

Zika microneutralization test-positive samples, the cross-reactivity was 3% to 13%. The initial 

99% did not involve Zika-positive samples. A manuscript on these results is in preparation.

Sanofi is co-developing with a biotech company in San Diego an RDT IgG test that could be 

used for pre-vaccination screening, which they plan to submit for FDA clearance.

WHO also is working on a Target Product Profile (TPP) project. The optimal pre-vaccination 

screening test would be a low-cost RDT that could be performed on whole blood from a 

fingerstick sample. The minimum sensitivity and specificity would be >90%. The optimal 

reference panel would include curated specimens that are positive for dengue, other flavivirus, 

and dengue plus previous flavivirus samples at varying time points after infection, as well as a 

variety of flavivirus vaccine recipients.

The WG will be completing the EtR framework and GRADE analyses over the next few months 

in order to make recommendations to ACIP. The topics covered will include CYD-TDV costeffectiveness studies, acceptability, implementation issues, and an update of any information 

available on laboratory tests. In formulating recommendations, the WG will need to consider 

overall cost-effectiveness given the unusual requirement for pre-vaccination screening, and best 

information on the sensitive and specificity of available tests. Hopefully, an independent 

evaluation of available IgG laboratory tests using close to optimum serum panels can be 

conducted in the near future. The confidence in cost-effectiveness and predictive value 

estimates will improve with updated population representative seroprevalence data. CYD will 

clearly need to be explained to the population through immunization program outreach and 

implemented with carefully vetted informed consent language. It will be necessary to determine 

what the feasible logistics are of pre-vaccination screening in the US territories, and whether 

there is a strong territorial program for vaccinating school age children. With better 

seroprevalence data, the optimal age for vaccination might need to be adjusted. It also seems 

worth considering identifying subpopulations living in the US from endemic areas who frequently 

return to endemic areas to visit friends and relatives (e.g., Puerto Ricans in Florida and New 

York or Latino populations living on the highly mobile US Mexico border). 

Discussion Questions

Dr. Hunter said that Dr. Waterman’s summary of what the WG is addressing and thinks that the 

important issues are was very reassuring to him. The goal of achieving >90% sensitivity and 

specificity is key, though it will likely be quite a challenge. It would be nice to have some hard 

data on whether that works in an implementable way.

Dr. Romero asked whether a higher level of informed consent would be required and if so, what 

the impact of this would be on patient/physician interaction.

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Dr. Messonnier asked whether the local AAP chapter was involved in these discussions. 

Clearly, a major issue regarded the feasibility of implementation in Puerto Rico. Using all of the 

appropriate channels to answer that question seems quite important.

Dr. Kimberlin (AAP) responded that they had not begun those conversations yet, but this 

presentation would give them the opportunity to do so during AAP’s Fall Committee on 

Infectious Diseases (COID) meeting. They also have a liaison representative on the Sociedad 

Latinoamericana de Infectologia Pediatrica (SLIPE), which is the Latin American Society of 

Pediatric Infectious Diseases. The SLIPE representative is Puerto Rican. He thought the 

recommendation to obtain more input from people who live in the areas that would be impacted 

by the recommendations was a fantastic suggestion.

Dr. Talbot thought it would be helpful for ACIP for someone other than Sanofi Pasteur to review 

what occurred in the Philippines in order to answer the pending questions and put some of the 

concerns to rest.

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Upon reviewing the foregoing version of the June 26-27, 2019 ACIP meeting minutes, Dr. José

Romero, ACIP Chair, certified that to the best of his knowledge, they are accurate and 

complete. His original, signed certification is on file with the Federal Advisory Committee Act 

Program Unit, Strategic Initiatives Business (SBI).

Certification

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Department of Health and Human Services

Centers for Disease Control and Prevention

Advisory Committee on Immunization Practices

November 2018 – June 30, 2019

CHAIR

ROMERO, José R., MD, FAAP

Professor of Pediatrics

Horace C. Cabe Endowed Chair in Infectious Diseases

Director, Pediatric Infectious Diseases Section

University of Arkansas for Medical Sciences and Arkansas Children's Hospital 

Director, Clinical Trials Research

Arkansas Children's Hospital Research Institute

Little Rock, AR

Term: 10/30/2018-06/30/2021

EXECUTIVE SECRETARY

COHN, Amanda, MD

Senior Advisor for Vaccines 

National Center for Immunization and Respiratory Diseases

Centers for Disease Control and Prevention

Atlanta, GA

MEMBERS

ATMAR, Robert L., MD

John S. Dunn Clinical Research Professor in Infectious Diseases

Departments of Medicine and Molecular Virology & Microbiology 

Baylor College of Medicine 

Chief, Infectious Diseases Service

Ben Taub General Hospital, Harris Health System

Houston, TX

Term: 7/1/2016 – 6/30/2020

AULT, Kevin A., MD, FACOG, FIDSA 

Professor and Division Director

Department of Obstetrics and Gynecology

University of Kansas Medical Center 

Kansas City, KS

Term: 10/26/2018 – 6/30/2022

BERNSTEIN, Henry, DO, MHCM, FAAP

Professor of Pediatrics

Zucker School of Medicine at Hofstra/Northwell

Cohen Children’s Medical Center

New Hyde Park, NY

Term: 11/27/2017-06/30/2021

ACIP Membership Roster

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EZEANOLUE, Echezona, MD, MPH 

Professor of Pediatrics and Public Health

Department of Epidemiology and Biostatistics

Director, Global Health and Implementation Research Initiatives

University of Nevada

Las Vegas, NV

Term: 07/01/2015-06/30/2019

FREY, Sharon E., M.D.

Professor and Associate Director of Clinical Research

Clinical Director, Center for Vaccine Development

Division of Infectious Diseases, Allergy and Immunology

Saint Louis University Medical School

Saint Louis, MO

Term: 11/27/2017-06/30/2021

GRAVENSTEIN, Stefan, MD, MPH 

Professor of Medicine and Health Services Policy and Practice

Brown University

Associate Director, Center of Innovation for Long-Term Care Services and Supports

Providence Veterans Administration Hospital

Providence, RI

Term: 10/26/18 - 6/30/2022

HUNTER, Paul, MD

Associate Professor of Family Medicine and Community Health

University of Wisconsin School of Medicine and Public Health

Associate Medical Director 

City of Milwaukee Health Department

Milwaukee, WI

Term: 7/1/2016 – 6/30/2020

LEE, Grace M., MD, MPH

Associate Chief Medical Officer for Practice Innovation

Lucile Packard Children’s Hospital

Professor of Pediatrics, Stanford University School of Medicine

Stanford, CA

Term: 7/1/2016 – 6/30/2020

MCNALLY, Veronica V., JD

President and CEO

Franny Strong Foundation

West Bloomfield, Michigan

Term: 10/31/2018 – 6/30/2022

MOORE, Kelly, MD, MPH,

Assistant Clinical Professor, Department of Health Policy 

Vanderbilt University School of Medicine 

Nashville, TN

Term: 07/01/2015-06/30/2019

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STEPHENS, David, MD 

Professor of Medicine, Division of Infectious Diseases 

Chair, Department of Medicine 

Emory University School of Medicine 

Emory University 

Atlanta, GA 

Term: 07/01/2015-06/30/2019

SZILAGYI, Peter, MD, MPH 

Professor of Pediatrics

Executive Vice-Chair and Vice-Chair for Research

Department of Pediatrics 

University of California, Los Angeles (UCLA)

Los Angeles, California

Term: 7/1/2016 – 6/30-2020

TALBOT, Helen Keipp, MD

Associate Professor of Medicine

Vanderbilt University

Nashville, TN

Term: 10/29/2018 – 6/30/2022

WALTER, Emmanuel (Chip), Jr., MD, MPH

Professor of Pediatrics

Duke University School of Medicine

Durham, NC

Term: 07/01/2015-06/30/2019

EX OFFICIO MEMBERS

Centers for Medicare and Medicaid Services (CMS)

HANCE, Mary Beth

Senior Policy Advisor

Division of Quality, Evaluations and Health Outcomes

Children and Adults Health Programs Group

Center for Medicaid, CHIP and Survey & Certification

Centers for Medicare and Medicaid Services

Baltimore, MD

Department of Defense (DoD)

DEUSSING, ERIC, MD, MPH

Commander, Medical Corps, United States Navy

Department of Defense Liaison

Centers for Disease Control and Prevention

Atlanta, GA

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Department of Veterans Affairs (DVA)

KIM, Jane A., MD, MPH

Deputy Chief Consultant for Preventive Medicine

Office of Patient Care Services

National Center for Health Promotion and Disease Prevention

Durham, North Carolina 

Food and Drug Administration (FDA) 

FINK, Doran, MD, PhD

Deputy Director, Clinical, Division of Vaccines and Related Products Applications

Office of Vaccines Research and Review

Center for Biologics Evaluation and Research

Food and Drug Administration

Silver Spring, MD

Health Resources and Services Administration (HRSA)

NAIR, Narayan, MD

CAPT, USPHS

Division Director/Chief Medical Officer

Division of Injury Compensation Programs

Healthcare Systems Bureau

Rockville, MD

Indian Health Service (IHS)

WEISER, Thomas, MD, MPH

Medical Epidemiologist

Portland Area Indian Health Service

Portland, OR

National Vaccine Program Office (NVPO)

BECKHAM, Tammy

Acting Director

National Institutes of Health (NIH)

BEIGEL, John, M.D.

Associate Director for Clinical Research

Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases (NIAID)

Bethesda, MD

LIAISON REPRESENTATIVES

American Academy of Family Physicians (AAFP)

ROCKWELL, Pamela G., D.O.

Associate Professor, Department of Family Medicine,

University of Michigan Medical School

Medical Director, Dominos Farms Family Medicine

Ann Arbor, MI

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American Academy of Pediatrics (AAP)

MALDONADO, Yvonne, MD

Senior Associate Dean for Faculty Development and Diversity

Professor of Pediatrics and Health Research and Policy

Chief, Division of Pediatric Infectious Diseases

Stanford University School of Medicine

Stanford, CA

American Academy of Pediatrics (AAP)

Red Book Editor 

KIMBERLIN, David, MD

Professor of Pediatrics

Division of Pediatric Infectious Diseases

The University of Alabama at Birmingham School of Medicine

Birmingham, AL

American Academy of Physician Assistants (AAPA)

LÉGER, Marie-Michèle, MPH, PA-C 

Senior Director, Clinical and Health Affairs

American Academy of Physician Assistants

Alexandria, VA

American College Health Association (ACHA)

EVEN, Susan, MD

Executive Director

Student Health Center

University of Missouri

Columbia, MO

American College of Nurse Midwives (ACNM)

HAYES, Carol E., CNM, MN, MPH

Lead Clinician

Clinical Quality Compliance and Management

Planned Parenthood Southeast 

Atlanta, GA

American College of Nurse Midwives (ACNM) (alternate)

MEHARRY, Pamela M., PHD, CNM

Midwifery Educator, Human Resources for Health

In partnership with University of Rwanda and University of Illinois, Chicago

American College of Obstetricians and Gynecologists (ACOG)

American College of Physicians (ACP)

GOLDMAN, Jason M. MD, FACP

Affiliate Assistant Professor of Clinical Biomedical Science, Florida Atlantic University, Boca 

Raton, Florida

Private Practice

Coral Springs, FL

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American Geriatrics Society (AGS)

SCHMADER, Kenneth, MD

Professor of Medicine-Geriatrics

Geriatrics Division Chief

Duke University and Durham VA Medical Centers

Durham, NC

America’s Health Insurance Plans (AHIP)

NETOSKIE, Mark J., MD, MBA

Market Medical Executive, CIGNA 

Houston, TX

American Immunization Registry Association (AIRA)

COYLE, Rebecca, MSEd

Executive Director, AIRA

Washington, DC

American Medical Association (AMA)

FRYHOFER, Sandra Adamson, MD

Adjunct Associate Professor of Medicine

Emory University School of Medicine

Atlanta, GA

American Nurses Association (ANA)

RITTLE, Charles (Chad), DNP, MPH, RN

Assistant Professor, Nursing Faculty

Chatham University, School of Health Sciences

Pittsburgh, PA

American Osteopathic Association (AOA)

GROGG, Stanley E., DO

Associate Dean/Professor of Pediatrics

Oklahoma State University-Center for Health Sciences

Tulsa, OK

American Pharmacists Association (APhA)

FOSTER, Stephan L., PharmD

CAPT (Ret) U.S.P.H.S.

Professor, College of Pharmacy

University of Tennessee Health Sciences Center

Memphis, TN

Association of Immunization Managers (AIM)

FINLEY, Christine, RN, MPH 

Immunization Program Manager 

Vermont Department of Health

Burlington, VT

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Association for Prevention Teaching and Research (APTR)

McKINNEY, W. Paul, MD

Professor and Associate Dean

University of Louisville School of Public Health and Information Sciences

Louisville, KY

Association of State and Territorial Health Officials (ASTHO)

SMITH, Nathaniel, MD, MPH

Director and State Health Officer

Arkansas Department of Health

Little Rock, AR

Biotechnology Industry Organization (BIO)

ARTHUR, Phyllis A., MBA

Senior Director, Vaccines, Immunotherapeutics and Diagnostics Policy

Washington, DC 

Council of State and Territorial Epidemiologists (CSTE) 

HAHN, Christine, MD

State Epidemiologist

Office of Epidemiology, Food Protection and Immunization

Idaho Department of Health and Welfare

Boise, ID

Council of State and Territorial Epidemiologists (CSTE) (alternate)

LETT, Susan, MD, MPH

Medical Director, Immunization Program

Division of Epidemiology and Immunization

Massachusetts Department of Public Health

Boston, MA

Canadian National Advisory Committee on Immunization (NACI)

QUACH, Caroline, MD, MSc

Pediatric Infectious Disease Specialist and Medical Microbiologist 

Medical Lead, Infection Prevention and Control Unit 

Medical Co-director – Laboratory Medicine, Optilab

Montreal-CHUM

Montreal, Québec, Canada

Infectious Diseases Society of America (IDSA) 

BAKER, Carol J., MD

Professor of Pediatrics

Molecular Virology and Microbiology

Baylor College of Medicine

Houston, TX

National Association of County and City Health Officials (NACCHO)

ZAHN, Matthew, MD

Medical Director, Epidemiology

Orange County Health Care Agency

Santa Ana, CA

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National Association of County and City Health Officials (NACCHO) (alternate)

DUCHIN, Jeffrey, MD

Health Officer and Chief, Communicable Disease Epidemiology and Immunization Section 

Public Health - Seattle and King County

Professor in Medicine 

Division of Allergy and Infectious Diseases

University of Washington School of Medicine and School of Public Health

Seattle, WA

National Association of Pediatric Nurse Practitioners (NAPNAP)

STINCHFIELD, Patricia A., RN, MS, CPNP

Director

Infectious Disease/Immunology/Infection Control 

Children's Hospitals and Clinics of Minnesota

St. Paul, MN

National Foundation for Infectious Diseases (NFID)

SCHAFFNER, William, MD

Chairman, Department of Preventive Medicine

Vanderbilt University School of Medicine

Nashville, TN

National Immunization Council and Child Health Program, Mexico

DURAN, Luis, MD

Director, Center for Children and Adolescent Health (CeNSIA)

Ministry of Health / Secretaría de Salud

Mexico

National Medical Association (NMA)

WHITLEY-WILLIAMS, Patricia, MD

Professor and Chair

University of Medicine and Dentistry of New Jersey

Robert Wood Johnson Medical School 

New Brunswick, NJ

Pediatric Infectious Diseases Society (PIDS)

O’LEARY, Sean, MD, MPH

Associate Professor of Pediatrics

Pediatric Infectious Diseases

General Academic Pediatrics

Children’s Hospital Colorado

University of Colorado School of Medicine

Pediatric Infectious Diseases Society (PIDS) (alternate)

SAWYER, Mark H, MD

Professor of Clinical Pediatrics

University of California, San Diego School of Medicine

San Diego, CA

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Pharmaceutical Research and Manufacturers of America (PhRMA)

ROBERTSON, Corey, MD, MPH 

Senior Director, US Medical, Sanofi Pasteur 

Swiftwater, PA

Society for Adolescent Health and Medicine (SAHM)

MIDDLEMAN, Amy B., MD, MSEd, MPH

Professor of Pediatrics

Chief, Section of Adolescent Medicine

University of Oklahoma Health Sciences Center

Oklahoma City, OK

Society for Healthcare Epidemiology of America (SHEA)

WEBER, David, MD, MPH

Professor of Medicine, Pediatrics, and Epidemiology

University of North Carolina Schools of Medicine and Public Health

Medical Director, Hospital Epidemiology and Occupational Health, UNC Health Care

University of North Carolina

Chapel Hill, NC

This document has been archived for historical purposes. (7/1/2019) 

https://www.cdc.gov/vaccines/acip/meetings/downloads/min-archive/min-2019-06-508.pdf